12TH INTERNATIONAL CONFERENCE ON ALZHEIMER’S DRUG … · The Alzheimer’s Drug Discovery Foundation organizes two annual international scientific conferences as ... The Discovery

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September 26-27, 2011 Jersey City, NJ

12TH INTERNATIONALCONFERENCE ON

ALZHEIMER’SDRUG DISCOVERY

www.alzdiscovery.org

The Alzheimer’s Drug Discovery Foundation presents:

12th International Conference on Alzheimer’s Drug Discovery 1

TABLE OF CONTENTS

Welcome 2About the Alzheimer’s Drug Discovery Foundation 3Program 4Conference Sponsors 62011 ADDF Young Investigator Scholarship Recipients 8Bios and Abstracts 15

Carmela R. Abraham, PhD, Boston University School of Medicine 39

Karl-Heinz Braunewell, PhD, Southern Research Institute 41

Gabriela Chiosis, PhD, Memorial Sloan Kettering Cancer Center 33

Chad Dickey, PhD, University of South Florida 21

Karen Duff, PhD, Columbia University 24

Howard Fillit, MD, Alzheimer’s Drug Discovery Foundation 15

Illana Gozes, PhD, Allon Therapeutics Inc. 19

William Hu, MD, PhD, Emory University School of Medicine 47

Rakez Kayed, PhD, University of Texas Medical Branch 23

Jeff Kuret, PhD, Ohio State University 22

Donald C. Lo, PhD, Duke University Medical Center 28

José A. Luchsinger, MD, MPH, Columbia University 49

Robert W. Mahley, MD, PhD, Gladstone Institute of Neurological Disease & University of California, San Francisco 29

Pavel A. Petukhov, PhD, University of Illinois at Chicago 40

Allen Reitz, PhD, ALS Biopharma, LLC 30

Allen D. Roses, MD, FRCP (hon.), Duke University 46

Diana Shineman, PhD, Alzheimer's Drug Discovery Foundation 34

Judith Siuciak, PhD, The Biomarkers Consortium, Foundation for the National Institutes of Health 48

Daniel M. Skovronsky, MD, PhD, Avid Radiopharmaceuticals, Inc. 17

Grace E. Stutzmann, PhD, Rosalind Franklin University School of Medicine 38

Zhiqun Tan, MD, PhD, University of California, Irvine 42

Eugenia Trushina, PhD, Mayo Clinic College of Medicine 37

D. Martin Watterson, PhD, Northwestern University 26

Ryan J. Watts, PhD, Genentech 35

Tim West, PhD, C2N Diagnostics 45

Brandon Wustman, PhD, Amicus Therapeutics, Inc. 31

2

WELCOME

Pharmaceuticals, Inc.Gmbpartners for their contribution. Our sincere appreciation also extends to all of our speakers and chairs forthe hard work they do to accelerate drug discovery for Alzheimer’s disease and related deme

I am pleased to report that we received a record number of scholarship applications to attend this year’smeeting. Engaging the next generation of research scientists in the field is more important than ever soplease visit their poster presentatiopursuing their work in the field.

To help us plan an even better conference in 2012, please complete the survey to provide us with feedbackand suggestions.

Welcome, once again, to the

Best Regards,

Howard Fillit, MDExecutive DirectorAlzheimer’s Drug Discovery Foundation

WELCOME

Pharmaceuticals, Inc.GmbH; Abbott Laboratories; and Genentech.partners for their contribution. Our sincere appreciation also extends to all of our speakers and chairs forthe hard work they do to accelerate drug discovery for Alzheimer’s disease and related deme




Best Regards,


WELCOME

On behalf of the Alzheimer’s Drug Discovery Foundation (ADDF), I am pleased towelcome you to our

For more than a decade now, our annual meeting has brought together scientistsintent on accelerating the development of treatments for Alzheimer's disease andrelated dementias, while creating opportunities for networking between academia,govus one step closer to accomplishing our mission and maintaining our singularfocus on the science that is needed to conquer the disease.

We are deeply grateful to our generousmeeting possible: Pfizer Inc.; Merck Research Laboratories; Lilly USA, LLC; Elan

Pharmaceuticals, Inc.; Allon Therapeutics, Inc.; NeuroPhage Pharmaceuticals, Inc.; JSW Lifesciences; Abbott Laboratories; and Genentech.

partners for their contribution. Our sincere appreciation also extends to all of our speakers and chairs forthe hard work they do to accelerate drug discovery for Alzheimer’s disease and related deme




Best Regards,


On behalf of the Alzheimer’s Drug Discovery Foundation (ADDF), I am pleased towelcome you to our

For more than a decade now, our annual meeting has brought together scientistsintent on accelerating the development of treatments for Alzheimer's disease andrelated dementias, while creating opportunities for networking between academia,government, and biotechnology and pharmaceutical companies. Each year bringsus one step closer to accomplishing our mission and maintaining our singularfocus on the science that is needed to conquer the disease.


Allon Therapeutics, Inc.; NeuroPhage Pharmaceuticals, Inc.; JSW Lifesciences; Abbott Laboratories; and Genentech.


I am pleased to report that we received a record number of scholarship applications to attend this year’smeeting. Engaging the next generation of research scientists in the field is more important than ever soplease visit their poster presentations. We are proud of their efforts and encourage them to continuepursuing their work in the field.

To help us plan an even better conference in 2012, please complete the survey to provide us with feedback

Welcome, once again, to the 12th International Conference on Alzheimer’s Drug Discovery

Alzheimer’s Drug Discovery Foundation

On behalf of the Alzheimer’s Drug Discovery Foundation (ADDF), I am pleased towelcome you to our 12th International Conference on Alzheimer’s Drug

For more than a decade now, our annual meeting has brought together scientistsintent on accelerating the development of treatments for Alzheimer's disease andrelated dementias, while creating opportunities for networking between academia,

ernment, and biotechnology and pharmaceutical companies. Each year bringsus one step closer to accomplishing our mission and maintaining our singularfocus on the science that is needed to conquer the disease.


Allon Therapeutics, Inc.; NeuroPhage Pharmaceuticals, Inc.; JSW Lifesciences; Abbott Laboratories; and Genentech.


I am pleased to report that we received a record number of scholarship applications to attend this year’smeeting. Engaging the next generation of research scientists in the field is more important than ever so

ns. We are proud of their efforts and encourage them to continue


2th International Conference on Alzheimer’s Drug Discovery


On behalf of the Alzheimer’s Drug Discovery Foundation (ADDF), I am pleased to12th International Conference on Alzheimer’s Drug




Allon Therapeutics, Inc.; NeuroPhage Pharmaceuticals, Inc.; JSW LifesciencesWe would also like to thank our exhibitors and media









We are deeply grateful to our generous sponsors whose support makes thismeeting possible: Pfizer Inc.; Merck Research Laboratories; Lilly USA, LLC; Elan










sponsors whose support makes thismeeting possible: Pfizer Inc.; Merck Research Laboratories; Lilly USA, LLC; Elan












partners for their contribution. Our sincere appreciation also extends to all of our speakers and chairs forthe hard work they do to accelerate drug discovery for Alzheimer’s disease and related dementias.




2th International Conference on Alzheimer’s Drug Discovery!

On behalf of the Alzheimer’s Drug Discovery Foundation (ADDF), I am pleased to12th International Conference on Alzheimer’s Drug Discovery.


ernment, and biotechnology and pharmaceutical companies. Each year bringsus one step closer to accomplishing our mission and maintaining our singular



partners for their contribution. Our sincere appreciation also extends to all of our speakers and chairs forntias.




On behalf of the Alzheimer’s Drug Discovery Foundation (ADDF), I am pleased to


ernment, and biotechnology and pharmaceutical companies. Each year bringsus one step closer to accomplishing our mission and maintaining our singular



partners for their contribution. Our sincere appreciation also extends to all of our speakers and chairs for





ABOUT THE ALZHEIMER’S DRUG DISCOVERY FOUNDATION

MISSION

The Alzheimer’s Drug Discovery Foundation’s (ADDF) sole mission is to rapidly accelerate the discoveryand development of drugs to prevent, treat and cure Alzheimer’s disease (AD), related dementias andcognitive aging.

The Alzheimer’s Drug Discovery Foundation was established in 2004 to expand upon the programsinitiated by the Institute for the Study of Aging (ISOA) Inc., a private foundation founded by the EstéeLauder family in 1998. We use a venture philanthropy investment model to bridge the global funding gapbetween basic research and later-stage development, recycling any return on investment to support newresearch.

The ADDF has granted more than $50 million to fund over 340 Alzheimer’s drug discovery programs andclinical trials in academic centers and biotechnology companies in 18 countries. Scientists funded by theADDF have tested over 30 new drugs in people with Alzheimer’s disease. Subsequent to the ADDF’scritical initial funding, our grantees have received commitments of over $2 billion in follow-on funding fromgovernment, pharmaceutical companies and venture capital firms to further advance their drug research.

OUR CONFERENCES

The Alzheimer’s Drug Discovery Foundation organizes two annual international scientific conferences aspart of our ongoing efforts to increase researchers’ knowledge about Alzheimer’s disease and the drugdiscovery process. The conferences promote networking to catalyze the exchange of ideas and fosteralliances that accelerate the development of new treatments for AD.

Our annual International Conference for Alzheimer’s Drug Discovery, held in the fall, focuses on thediscovery and development of drugs targeting Alzheimer's disease and related dementias. The DrugDiscovery for Neurodegeneration conference, held in the winter, is designed to educate scientists on theprocess of translating basic neuroscience research into innovative therapies. The Alzheimer’s DrugDiscovery Foundation also plans smaller “catalyst conferences” that center around a relevant topic in thefield of neurodegeneration.

Alzheimer’sDrug Discovery

Foundation

4

PROGRAM

Monday, September 268:00 – 8:30am Registration & Continental Breakfast

8:30 – 8:50Welcome & Opening RemarksHoward Fillit, MD, Alzheimer's Drug Discovery Foundation

8:50 – 9:30PLENARY: From Academic Discovery Towards an FDA Approval for a Novel Amyloid Imaging AgentDaniel M. Skovronsky, MD, PhD, Avid Radiopharmaceuticals, Inc.

I. Targeting Tau for Alzheimer’s Disease and Related DementiasChair: Illana Gozes, PhD, Allon Therapeutics Inc.

9:30 – 9:35 Session Overview – Illana Gozes, PhD, Allon Therapeutics Inc.

9:35 – 9:55The Discovery and Preclinical Progress of the Neuroprotective Peptide, davunetide, in the Treatment ofTauopathiesIllana Gozes, PhD, Allon Therapeutics Inc.

9:55 – 10:05 Q&A

10:05 – 10:25Modulating the Hsp70/DnaJ Protein Interface to Dictate Triage Decisions for TauChad Dickey, PhD, University of South Florida

10:25 – 10:35 Q&A10:35 – 11:05 BREAK

11:05 – 11:25Developing a Tau Imaging Agent for Alzheimer’s DiseaseJeff Kuret, PhD, Ohio State University

11:25 – 11:35 Q&A

11:35 – 11:55Targeting Tau Oligomers through ImmunotherapyRakez Kayed, PhD, University of Texas Medical Branch

11:55 am –12:05 pm Q&A

12:05 – 12:25Tau Clearance by AutophagyKaren Duff, PhD, Columbia University

12:25 – 12:35 Q&A12:35 – 1:30 LUNCH & POSTER SESSION

II. Inflammation, Chaperones and Novel TargetsChair: D. Martin Watterson, PhD, Northwestern University

1:30 – 1:35 Session Overview – D. Martin Watterson, PhD, Northwestern University

1:35 – 1:55Design and Refinement of Novel Small Molecule Compounds Targeting Proinflammatory CytokineOverproduction: A Potential Disease-Modifying Therapeutic Approach to CNS DiseasesD. Martin Watterson, PhD, Northwestern University

1:55 – 2:05 Q&A

2:05 – 2:25Optimizing New Drug Candidates for Protein Disulfide Isomerase, A Novel Target for NeurodegenerativeDiseasesDonald C. Lo, PhD, Duke University Medical Center

2:25 – 2:35 Q&A

2:35 – 2:55

Proof-of-Concept That Small Molecule Structure Correctors Are Capable of Abolishing the DetrimentalEffects of Apolipoprotein E4 in Vitro by Inhibiting Domain InteractionRobert W. Mahley, MD, PhD, Gladstone Institute of Neurological Disease and University of California, SanFrancisco

2:55 – 3:05 Q&A3:05 – 3:35 BREAK

3:35 – 3:55Tau Lowering Agents for the Treatment of Alzheimer’s DiseaseAllen Reitz, PhD, ALS Biopharma, LLC

3:55 – 4:05 Q&A

4:05 – 4:25Modulation of Ganglioside Catabolism Using Pharmacological Chaperones: A Novel TherapeuticApproach for Alzheimer’s DiseaseBrandon Wustman, PhD, Amicus Therapeutics, Inc.

4:25 – 4:35 Q&A

4:35 – 4:55Heat Shock Protein 90 in Neurodegenerative DiseasesGabriela Chiosis, PhD, Memorial Sloan Kettering Cancer Center

4:55 – 5:05 Q&A

5:05 – 5:10Closing RemarksDiana Shineman, PhD, Alzheimer's Drug Discovery Foundation

5:10 – 7:00 NETWORKING RECEPTION & POSTER SESSION


Tuesday, September 278:00 – 8:30 am Continental Breakfast

8:30 – 9:10PLENARY: Enhancing CNS Uptake of Biologics through Molecular EngineeringRyan J. Watts, PhD, Genentech

III. Neuroprotection and Synaptic EnhancementChair: Howard Fillit, MD, Alzheimer's Drug Discovery Foundation

9:10 – 9:15 Session Overview – Howard Fillit, MD, Alzheimer’s Drug Discovery Foundation

9:15 – 9:35Tricyclic Pyrone Compounds and Axonal Trafficking Dysfunction in ADEugenia Trushina, PhD, Mayo Clinic College of Medicine

9:35 – 9:45 Q&A

9:45 – 10:05Targeting Neuronal Calcium Signaling to Halt AD-linked Synaptic DysfunctionGrace E. Stutzmann, PhD, Rosalind Franklin University School of Medicine

10:05 – 10:15 Q&A

10:15 – 10:35Klotho Enhances Oligodendrocyte Maturation and MyelinationCarmela R. Abraham, PhD, Boston University School of Medicine

10:35 – 10:45 Q&A

10:45 – 11:15 BREAK

11:15 – 11:35Mapping the Binding Site of HDAC 2 for the Design of Novel HDAC Inhibitors Lacking Zinc Binding GroupPavel A. Petukhov, PhD, University of Illinois at Chicago

11:35 – 11:45 Q&A11:45 am–12:05 pm

Targeting the Neuronal Calcium Sensor (NCS) Protein, VILIP-1, for Cognitive Impairment in CNS DisordersKarl-Heinz Braunewell, PhD, Southern Research Institute

12:05 – 12:15 Q&A

12:15 – 12:35Efficacy of Herbal Extract, Tetramethylpyrazine, for Alzheimer’s DiseaseZhiqun Tan, MD, PhD, University of California, Irvine

12:35 – 12:45 Q&A12:45 – 1:45 LUNCH & POSTER SESSION

IV. Accelerating Clinical Trials for Alzheimer’s Disease through BiomarkersChair: Tim West, PhD, C2N Diagnostics

1:45 - 1:50 Session Overview – Tim West, PhD, C2N Diagnostics, Inc.

1:50 – 2:10A Novel Application of Stable Isotope Labeling for Disease Detection and Clinical Trials in Alzheimer’sTim West, PhD, C2N Diagnostics

2:10 – 2:20 Q&A

2:20 – 2:40TOMM40 Genetic Biomarker: Accelerating Drug Development for Alzheimer’s Disease and FrontotemporalDementiaAllen D. Roses, MD, FRCP (hon.), Duke University

2:40 – 2:50 Q&A

2:50 – 3:10CSF Biomarkers of FTLD-TDP and FTLD-Tau: A Multi-Center StudyWilliam Hu, MD, PhD, Emory University School of Medicine

3:10 – 3:20 Q&A3:20 – 3:50 BREAK

3:50 – 4:10Use of Targeted Multiplex Proteomic Strategies to Identify Plasma and Cerebral Spinal Fluid-BasedBiomarkers in Alzheimer’s DiseaseJudith Siuciak, PhD, The Biomarkers Consortium, Foundation for the National Institutes of Health

4:10 – 4:20 Q&A

4:20 – 4:40Pilot Trial of Metformin in the Prevention of Alzheimer’s DiseaseJosé A. Luchsinger, MD, MPH, Columbia University

4:40 – 4:50 Q&A

4:50 – 5:00Closing RemarksHoward Fillit, MD, Alzheimer's Drug Discovery Foundation

6

CONFERENCE

The

CONFERENCE

The Alzheimer’s Drug Discovery Foundation expresses its gratitude to t

CONFERENCE SPONSOR

Alzheimer’s Drug Discovery Foundation expresses its gratitude to t

www.merck.com

SPONSORS


www.pfizer.com

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www.pfizer.com

www.elan.com


www.pfizer.com

www.elan.com


www.pfizer.com

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2011 ADDF YOUNG INVESTIGATOR SCHOLARSHIPS

Congratulations to the recipients of the ADDF Young Investigator Scholarships! These scholarshipsrecognize the early achievements of talented young investigators by offering them the opportunity to attendthis conference and present posters of their work. Please visit the poster presentations during the breaks,lunch and networking reception.

The 2011 Young Investigator Scholars are:

Robin Barry Chan, PhD, Columbia University

Yi-Fang Chuang, MD, Johns Hopkins Bloomberg School of Public Health

Paige Elizabeth Cramer, BS, Case Western Reserve University

Kieren JM Egan, BS, University of Edinburgh

Akina Hoshino, BA, University of Maryland-Baltimore

Ali Jawaid, MD, University Hospital Zurich

Serene Keilani, PhD, Mount Sinai School of Medicine

Christopher Stephen Lewis, BS, University of Oklahoma

Tao Ma, MD, PhD, New York University

Carolina Andrea Oliva, PhD, Center for Aging and Regeneration CARE & Pontificia UniversidadCatólica de Chile

Marguerite Prior, PhD, Salk Institute for Biological Studies

Naoki Tajiri, PhD, University of South Florida College of Medicine

Michael J. Van Kanegan, PhD, Duke University Medical Center

Jason V. Wallach, BS, University of the Sciences

Kyle C. Wilcox, PhD, Northwestern University

Jiaqi Yao, MD, PhD, Weill Cornell Medical College

Daria Zamolodchikov, BA, The Rockefeller University

12th International Conference on Alzheimer’s Drug DiscoveryInternational Conference on Alzheimer’s Drug DiscoveryInternational Conference on Alzheimer’s Drug DiscoveryInternational Conference on Alzheimer’s Drug Discovery 9

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12

JSW is one of the leading experts in transgenic disease moels of neurodegenerativediseases.JSW maintains large colonies of well characterized mouse and rat moels coveringamyloid, tau and combined pathologies.JSW offers a unique in vivo drug sccreeningchemical entities, biologics or gene therapies.A real “one stop shop” for your drug development program in AD.

o large portfolio of behavioral paradigmso quantitative histological evaluation of drug effectso biochemicalo wide spectrum of molecular biological methods

JSW has tested hundreds of drug candidates and treatment approaches for ADmodels.Highest level of quality (GLP

JSW gratefully acknowledges the support provided by the Alzheimer’s Drug DiscoveryFoundation.

www.jswTel: +43 316 258111

is one of the leading experts in transgenic disease moels of neurodegenerative

maintains large colonies of well characterized mouse and rat moels coveringamyloid, tau and combined pathologies.

offers a unique in vivo drug sccreeningchemical entities, biologics or gene therapies.A real “one stop shop” for your drug development program in AD.

large portfolio of behavioral paradigmsquantitative histological evaluation of drug effectsbiochemical analyses of brain and CSF sampleswide spectrum of molecular biological methods

has tested hundreds of drug candidates and treatment approaches for AD

Highest level of quality (GLP

gratefully acknowledges the support provided by the Alzheimer’s Drug DiscoveryFoundation.

www.jsw-lifesciences.comTel: +43 316 258111

www.

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Highest level of quality (GLP-certified)

gratefully acknowledges the support provided by the Alzheimer’s Drug Discovery

lifesciences.comTel: +43 316 258111

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Company database

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offers a unique in vivo drug sccreening platform to evaluate the effects of newchemical entities, biologics or gene therapies.A real “one stop shop” for your drug development program in AD.




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maintains large colonies of well characterized mouse and rat moels covering

platform to evaluate the effects of new

A real “one stop shop” for your drug development program in AD.

quantitative histological evaluation of drug effectsanalyses of brain and CSF samples

wide spectrum of molecular biological methodshas tested hundreds of drug candidates and treatment approaches for AD

Years of experience


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Subscribeaccess to each installment of essentialreading for scientists at the leading edge ofAlzheimer’s disease research.

Stay on top of breakineurodegenerativewide as covered by our experienced newsteam. We are tracking discoveries from theblockbusters to the obscure. Our reportersferret out the important details, place them incontext, and as

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Subscribe to our weekly email digest for easyaccess to each installment of essentialreading for scientists at the leading edge ofAlzheimer’s disease research.

on top of breakineurodegenerativewide as covered by our experienced newsteam. We are tracking discoveries from theblockbusters to the obscure. Our reportersferret out the important details, place them incontext, and ask probing questions about the


Participate in the community of scientistsregularly commenting on new research,asking questions, discussing interpretations,

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to our weekly email digest for easyaccess to each installment of essentialreading for scientists at the leading edge ofAlzheimer’s disease research.

on top of breaking developments indisease research world

wide as covered by our experienced newsteam. We are tracking discoveries from theblockbusters to the obscure. Our reportersferret out the important details, place them in

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to our weekly email digest for easyaccess to each installment of essentialreading for scientists at the leading edge of

ng developments indisease research world-

wide as covered by our experienced newsteam. We are tracking discoveries from theblockbusters to the obscure. Our reportersferret out the important details, place them in

k probing questions about the

in the community of scientistsregularly commenting on new research,

questions, discussing interpretations,wrestling over contradictions through-

discussions hosted byresearchers to debate and brain-

storm controversial new topics in real time.


14

OPPORTUNITIES FOR FUNDING

PROGRAM TO ACCELERATE CLINICALTRIALS (PACT)

The Alzheimer's Drug Discovery Foundation(ADDF) has created the Program to AccelerateClinical Trials (PACT) to increase the number ofinnovative drugs tested in humans at the crucialproof-of-concept stage for Alzheimer’sdisease. This program will primarily fundbiomarker outcome-based, Phase IIa pilotclinical trials for Alzheimer’s disease, althoughother clinical applications may also beconsidered.

THE ADDF/BELFER APOE THERAPEUTICSINNOVATION PROGRAM

The Alzheimer’s Drug Discovery Foundation(ADDF) and the Robert A. and Renée E.Belfer Family Foundation established TheADDF/Belfer ApoE Therapeutics InnovationProgram to accelerate the development ofnovel therapeutics specifically designed totarget apoE pathological mechanisms. Thisprogram will support both preclinical andclinical stage programs.

GENERAL REQUEST FOR PROPOALSThe ADDF General RFP funds drug discovery and development research programs in the field of

Alzheimer’s disease, related dementias and cognitive aging in academic centers andbiotechnology companies worldwide. The ADDF does not support basic research and solely

allocate funding towards translational research efforts.

QUARTERLY DEADLINES FOR ALL PROGRAMSFor more information or to apply for funding, please visit:

www.alzdiscovery.org/index.php/research-programs/grant-opportunities

For program related inquiries, please contact:

Diana Shineman, PhDAssistant Director, Scientific Affairs

Phone: [email protected]

For application inquiries, please contact:

Niyati ThakkerGrants Assistant

Phone: [email protected]

Alzheimer’sDrug Discovery

Foundation


BIOS AND ABSTRACTS

16

CONFERENCE CHAIRHoward Fillit, MD

Corporate Medical Director for Medicare at New York Life, responsible for over 125,000 Medicaremanaged care members in five regional markets. He is the author or coand clinical publications, aand GerontologyLifetime Achievementand biotechnology companies, health care organizations and philanthropies.

CONFERENCE CHAIRHoward Fillit, MD

Corporate Medical Director for Medicare at New York Life, responsible for over 125,000 Medicaremanaged care members in five regional markets. He is the author or coand clinical publications, aand GerontologyLifetime Achievementand biotechnology companies, health care organizations and philanthropies.

CONFERENCE CHAIRHoward Fillit, MD, Alzheimer’s Drug Discovery Foundation

Howard Fillit, MD, a geriatrician, neuroscientist and a leading expert in Alzheimer'sdisease, is the founding Executive Director of the Institute for thean Estée Lauder family foundation founded in 1998, and the Alzheimer’s Drug DiscoveryFoundation (ADDF), an affiliated public charity founded in 2004. ISOA and ADDF share acommon mission of accelerating drug discovery for Alzheimer’philanthropy. Dr. Fillit has had a distinguished academic mediRockefeller University and The Mount Sinai School of Medicine where he is a clinicalprofessor of geriatrics and medicine and professor of neurobiol

Corporate Medical Director for Medicare at New York Life, responsible for over 125,000 Medicaremanaged care members in five regional markets. He is the author or coand clinical publications, aand Gerontology. Dr. Fillit has received several awards and honors including theLifetime Achievement from the Alzheimer’s Association. He also servand biotechnology companies, health care organizations and philanthropies.

CONFERENCE CHAIRAlzheimer’s Drug Discovery Foundation


Corporate Medical Director for Medicare at New York Life, responsible for over 125,000 Medicaremanaged care members in five regional markets. He is the author or coand clinical publications, and is the senior editor of the leading international

. Dr. Fillit has received several awards and honors including thefrom the Alzheimer’s Association. He also serv

and biotechnology companies, health care organizations and philanthropies.



Corporate Medical Director for Medicare at New York Life, responsible for over 125,000 Medicaremanaged care members in five regional markets. He is the author or co

nd is the senior editor of the leading international. Dr. Fillit has received several awards and honors including the

from the Alzheimer’s Association. He also servand biotechnology companies, health care organizations and philanthropies.





from the Alzheimer’s Association. He also servand biotechnology companies, health care organizations and philanthropies.





from the Alzheimer’s Association. He also serves as a consultant to pharmaceuticaland biotechnology companies, health care organizations and philanthropies.


Howard Fillit, MD, a geriatrician, neuroscientist and a leading expert in Alzheimer'sdisease, is the founding Executive Director of the Institute for thean Estée Lauder family foundation founded in 1998, and the Alzheimer’s Drug DiscoveryFoundation (ADDF), an affiliated public charity founded in 2004. ISOA and ADDF share acommon mission of accelerating drug discovery for Alzheimer’s disease through venturephilanthropy. Dr. Fillit has had a distinguished academic mediRockefeller University and The Mount Sinai School of Medicine where he is a clinicalprofessor of geriatrics and medicine and professor of neurobiology. He was previously the

Corporate Medical Director for Medicare at New York Life, responsible for over 125,000 Medicaremanaged care members in five regional markets. He is the author or co-author of more than 250 scientific

nd is the senior editor of the leading international Textbook of Geriatric Medicine. Dr. Fillit has received several awards and honors including the Rita Hayworth Award for

es as a consultant to pharmaceuticaland biotechnology companies, health care organizations and philanthropies.

Howard Fillit, MD, a geriatrician, neuroscientist and a leading expert in Alzheimer'sdisease, is the founding Executive Director of the Institute for the Study of Aging (ISOA),an Estée Lauder family foundation founded in 1998, and the Alzheimer’s Drug DiscoveryFoundation (ADDF), an affiliated public charity founded in 2004. ISOA and ADDF share a

s disease through venturephilanthropy. Dr. Fillit has had a distinguished academic medical career at TheRockefeller University and The Mount Sinai School of Medicine where he is a clinical

ogy. He was previously theCorporate Medical Director for Medicare at New York Life, responsible for over 125,000 Medicare

author of more than 250 scientificTextbook of Geriatric Medicine

Rita Hayworth Award fores as a consultant to pharmaceutical

Howard Fillit, MD, a geriatrician, neuroscientist and a leading expert in Alzheimer'sStudy of Aging (ISOA),

an Estée Lauder family foundation founded in 1998, and the Alzheimer’s Drug DiscoveryFoundation (ADDF), an affiliated public charity founded in 2004. ISOA and ADDF share a

s disease through venturecareer at The

Rockefeller University and The Mount Sinai School of Medicine where he is a clinicalogy. He was previously the

Corporate Medical Director for Medicare at New York Life, responsible for over 125,000 Medicareauthor of more than 250 scientific

Textbook of Geriatric MedicineRita Hayworth Award for

es as a consultant to pharmaceutical

Howard Fillit, MD, a geriatrician, neuroscientist and a leading expert in Alzheimer'sStudy of Aging (ISOA),

an Estée Lauder family foundation founded in 1998, and the Alzheimer’s Drug DiscoveryFoundation (ADDF), an affiliated public charity founded in 2004. ISOA and ADDF share a

s disease through venturecareer at The

Rockefeller University and The Mount Sinai School of Medicine where he is a clinicalogy. He was previously the

Corporate Medical Director for Medicare at New York Life, responsible for over 125,000 Medicareauthor of more than 250 scientific

Textbook of Geriatric MedicineRita Hayworth Award for

es as a consultant to pharmaceutical


PLENARY SPEAKERDowned subsidiary of Eli Lilly and Company

Pennsylvania and did his undergraduate training in molecular biochemistry at Yale University.

Dr. Skovronsky was named by the Philadelphia Business Journal as one of their “Forty under Forty”business leaders in the region in 2006, by PharmaVoice magazine as one of the 100 top pharmaceuticalbusiness leaders in 2007, by Ernst & Young as the EntreprRegion in 2009 and Life Sciences CEO of the Year by the Philadelphia Business Journal in 2010. Avid wasnamed the Life Sciences Startup Company of the Year in 2007 by the Eastern Technology Council,received thnamed Best Incubator Company and Best LocalBusiness Journal. Avid's lead product candidate, Florbetapir (AVInnovation of 2011 by the Cleveland Clinic. Avid was acquired by Eli Lilly & Company in December of 2010for up to $800 million and now operates as a wholly owned subsidiary of Eli Lilly.

From Academic Discov

Daniel

Avid Radiopharmaceuticals, Inc.

Florbetapir F 18 has been studied in Phase I, Phase II and Phase III clinical trialsas a brain amyloid plaque imaging agent. Phase I studies determined the safetyand testII studiescognitively normal controls of variousneuropathological measurestracer retention intheseongoing longitudinal studies. Interim results from these studies will be presented, including anthe prognostic value of amyloid burden measured by florbetapirchanges in amyloid burden by florbetapirAlzheimer’s disease (including 11C


PLENARY SPEAKERDaniel M. Skovronskyowned subsidiary of Eli Lilly and Company


Dr. Skovronsky was named by the Philadelphia Business Journal as one of their “Forty under Forty”business leaders in the region in 2006, by PharmaVoice magazine as one of the 100 top pharmaceuticalbusiness leaders in 2007, by Ernst & Young as the EntreprRegion in 2009 and Life Sciences CEO of the Year by the Philadelphia Business Journal in 2010. Avid wasnamed the Life Sciences Startup Company of the Year in 2007 by the Eastern Technology Council,received the 2007 Frost & Sullivan Molecular Imaging Technology Innovation of the Year award and wasnamed Best Incubator Company and Best LocalBusiness Journal. Avid's lead product candidate, Florbetapir (AVInnovation of 2011 by the Cleveland Clinic. Avid was acquired by Eli Lilly & Company in December of 2010for up to $800 million and now operates as a wholly owned subsidiary of Eli Lilly.

From Academic Discov

Daniel M. Skovronsky


Florbetapir F 18 has been studied in Phase I, Phase II and Phase III clinical trialsas a brain amyloid plaque imaging agent. Phase I studies determined the safetyand test-retest reliability of the compound in healthy controls andII studies focused on crosscognitively normal controls of variousneuropathological measurestracer retention inthese completed Phase Iongoing longitudinal studies. Interim results from these studies will be presented, including anthe prognostic value of amyloid burden measured by florbetapirchanges in amyloid burden by florbetapirAlzheimer’s disease (including 11C


PLENARY SPEAKERaniel M. Skovronsky

owned subsidiary of Eli Lilly and Company

Dr. Skovronsky, President and CEO of Avid, founded the company and began operationsin mid-2005. Over the last six years, Dr. Skovronsky has led clinical programs inAlzheimer’s, Parkinson’s and Diabetes at Avid. Under Dr. Skovronsky’s leadership, Avidraised $70M in venture capital financing to support this research. Dr. Skovronsky hasmore than 40 publications in the field and has served as principle investigator onnumerous NIH research grants. Dr. Skovronsky trained as a resident in Pathology andcompleted a fellowship in Neuropathology at the Hospital of the University ofPennsylvania. Dr. Skovronsky received his


Dr. Skovronsky was named by the Philadelphia Business Journal as one of their “Forty under Forty”business leaders in the region in 2006, by PharmaVoice magazine as one of the 100 top pharmaceuticalbusiness leaders in 2007, by Ernst & Young as the EntreprRegion in 2009 and Life Sciences CEO of the Year by the Philadelphia Business Journal in 2010. Avid wasnamed the Life Sciences Startup Company of the Year in 2007 by the Eastern Technology Council,

e 2007 Frost & Sullivan Molecular Imaging Technology Innovation of the Year award and wasnamed Best Incubator Company and Best LocalBusiness Journal. Avid's lead product candidate, Florbetapir (AVInnovation of 2011 by the Cleveland Clinic. Avid was acquired by Eli Lilly & Company in December of 2010for up to $800 million and now operates as a wholly owned subsidiary of Eli Lilly.

From Academic Discovery T

M. Skovronsky


Florbetapir F 18 has been studied in Phase I, Phase II and Phase III clinical trialsas a brain amyloid plaque imaging agent. Phase I studies determined the safety

retest reliability of the compound in healthy controls andfocused on cross

cognitively normal controls of variousneuropathological measurestracer retention in the brain in vivo and amyloid pathology subsequently measured at autopsy. In addition to

completed Phase Iongoing longitudinal studies. Interim results from these studies will be presented, including anthe prognostic value of amyloid burden measured by florbetapirchanges in amyloid burden by florbetapirAlzheimer’s disease (including 11C


PLENARY SPEAKERaniel M. Skovronsky, MD,


Dr. Skovronsky, President and CEO of Avid, founded the company and began operations2005. Over the last six years, Dr. Skovronsky has led clinical programs in

Alzheimer’s, Parkinson’s and Diabetes at Avid. Under Dr. Skovronsky’s leadership, Avidsed $70M in venture capital financing to support this research. Dr. Skovronsky has

more than 40 publications in the field and has served as principle investigator onnumerous NIH research grants. Dr. Skovronsky trained as a resident in Pathology and

leted a fellowship in Neuropathology at the Hospital of the University ofPennsylvania. Dr. Skovronsky received his




ery Towards an FD

Avid Radiopharmaceuticals, Inc., a wholly


retest reliability of the compound in healthy controls andfocused on cross-sectional studies of AD

cognitively normal controls of variousneuropathological measures of amyloid pathology at autop

the brain in vivo and amyloid pathology subsequently measured at autopsy. In addition tocompleted Phase I – III registration studies, florbetapir F 18 is also being used in several

ongoing longitudinal studies. Interim results from these studies will be presented, including anthe prognostic value of amyloid burden measured by florbetapirchanges in amyloid burden by florbetapirAlzheimer’s disease (including 11C-PiB and CSF Abeta).

MD, PhD, Avid Radiopharmaceuticals, Inc.owned subsidiary of Eli Lilly and Company








owards an FDA Approval for a Novel Amyloid Imaging Agent

wholly-owned subsidiary of Eli Lilly and Company


retest reliability of the compound in healthy controls andsectional studies of AD

cognitively normal controls of various ages. The Phase III study compared in vivo imaging outcomes withof amyloid pathology at autop

the brain in vivo and amyloid pathology subsequently measured at autopsy. In addition toIII registration studies, florbetapir F 18 is also being used in several

ongoing longitudinal studies. Interim results from these studies will be presented, including anthe prognostic value of amyloid burden measured by florbetapirchanges in amyloid burden by florbetapir-PET and correlation of florbetapir

PiB and CSF Abeta).

Avid Radiopharmaceuticals, Inc.owned subsidiary of Eli Lilly and Company







e 2007 Frost & Sullivan Molecular Imaging Technology Innovation of the Year award and wasnamed Best Incubator Company and Best Local-Based-Research Company in 2010 by the PhiladelphiaBusiness Journal. Avid's lead product candidate, Florbetapir (AVInnovation of 2011 by the Cleveland Clinic. Avid was acquired by Eli Lilly & Company in December of 2010for up to $800 million and now operates as a wholly owned subsidiary of Eli Lilly.

A Approval for a Novel Amyloid Imaging Agent



retest reliability of the compound in healthy controls andsectional studies of AD subjects, mild cognitive impairment (MCI) subjects and

ages. The Phase III study compared in vivo imaging outcomes withof amyloid pathology at autopsy, and showed a significant correlation between


ongoing longitudinal studies. Interim results from these studies will be presented, including anthe prognostic value of amyloid burden measured by florbetapir

T and correlation of florbetapirPiB and CSF Abeta).





leted a fellowship in Neuropathology at the Hospital of the University ofPennsylvania. Dr. Skovronsky received his MD and


Dr. Skovronsky was named by the Philadelphia Business Journal as one of their “Forty under Forty”business leaders in the region in 2006, by PharmaVoice magazine as one of the 100 top pharmaceuticalbusiness leaders in 2007, by Ernst & Young as the Entrepreneur of the Year in the Greater PhiladelphiaRegion in 2009 and Life Sciences CEO of the Year by the Philadelphia Business Journal in 2010. Avid wasnamed the Life Sciences Startup Company of the Year in 2007 by the Eastern Technology Council,

e 2007 Frost & Sullivan Molecular Imaging Technology Innovation of the Year award and wasResearch Company in 2010 by the Philadelphia

Business Journal. Avid's lead product candidate, Florbetapir (AV-45),Innovation of 2011 by the Cleveland Clinic. Avid was acquired by Eli Lilly & Company in December of 2010for up to $800 million and now operates as a wholly owned subsidiary of Eli Lilly.




retest reliability of the compound in healthy controls and Alzheimer’s disease (AD) patients. Phasesubjects, mild cognitive impairment (MCI) subjects and

ages. The Phase III study compared in vivo imaging outcomes withsy, and showed a significant correlation between


ongoing longitudinal studies. Interim results from these studies will be presented, including anthe prognostic value of amyloid burden measured by florbetapir-PET, measurements

T and correlation of florbetapir





leted a fellowship in Neuropathology at the Hospital of the University ofand PhD from the University of


Dr. Skovronsky was named by the Philadelphia Business Journal as one of their “Forty under Forty”business leaders in the region in 2006, by PharmaVoice magazine as one of the 100 top pharmaceutical

eneur of the Year in the Greater PhiladelphiaRegion in 2009 and Life Sciences CEO of the Year by the Philadelphia Business Journal in 2010. Avid wasnamed the Life Sciences Startup Company of the Year in 2007 by the Eastern Technology Council,


45), was recently named the #1Innovation of 2011 by the Cleveland Clinic. Avid was acquired by Eli Lilly & Company in December of 2010for up to $800 million and now operates as a wholly owned subsidiary of Eli Lilly.



Florbetapir F 18 has been studied in Phase I, Phase II and Phase III clinical trials to supportas a brain amyloid plaque imaging agent. Phase I studies determined the safety profile, radiation dosimetry

Alzheimer’s disease (AD) patients. Phasesubjects, mild cognitive impairment (MCI) subjects and



ongoing longitudinal studies. Interim results from these studies will be presented, including anPET, measurements

T and correlation of florbetapir-PET with other biomarkers for

Avid Radiopharmaceuticals, Inc., a wholly




leted a fellowship in Neuropathology at the Hospital of the University offrom the University of





was recently named the #1Innovation of 2011 by the Cleveland Clinic. Avid was acquired by Eli Lilly & Company in December of 2010


owned subsidiary of Eli Lilly and Company, Philadelphia

to support developmentprofile, radiation dosimetry




ongoing longitudinal studies. Interim results from these studies will be presented, including anPET, measurements of longitudinal

with other biomarkers for

17

wholly-









, Philadelphia, PA

developmentprofile, radiation dosimetry



the brain in vivo and amyloid pathology subsequently measured at autopsy. In addition toIII registration studies, florbetapir F 18 is also being used in several large

ongoing longitudinal studies. Interim results from these studies will be presented, including an analysis ofof longitudinal










developmentprofile, radiation dosimetry



the brain in vivo and amyloid pathology subsequently measured at autopsy. In addition to

analysis ofof longitudinal


18

I. Targeting Tau for Alzheimer’s Disease and Related DementiasChair: Illana Gozes, PhD, Allon Therapeutics Inc.

The Discovery and Preclinical Progress of the Neuroprotective Peptide, davunetide, in theTreatment of TauopathiesIllana Gozes, PhD, Allon Therapeutics Inc.

Modulating the Hsp70/DnaJ Protein Interface to Dictate Triage Decisions for TauChad Dickey, PhD, University of South Florida

Developing a Tau Imaging Agent for Alzheimer’s DiseaseJeff Kuret, PhD, Ohio State University

Targeting Tau Oligomers through ImmunotherapyRakez Kayed, PhD, University of Texas Medical Branch

Tau Clearance by AutophagyKaren Duff, PhD, Columbia University


Illana Gozes, PhD

serving now as a member of the Board of Governors of Tel Aviv University, the Tel Aviv University Senate,the Scientific Review Board of the Alzheimer’s Drug Discovery Foundation (New York, USA), the ScientificReview Board of the Rett Foundation, memberAlzheimer’s Research and other Dementias, Peptides Research and Therapeutics, Pharmaceutical DrugDesign) and Past President of the Israel Society for Neuroscience.of the Journal of Molecular Neuroscience, the Secretary General of the European Neuropeptide Club andthe Chair of the Summer Neuropeptide Conference, The International Advisory Committee of VIP PACAPand Related Peptides and Chair of the 2011 Conf

Dr. Gozes is the scientific founder, Chief Scientific Officer of Allon Therapeutics, where she serves as amember of the Board of Directors. Allon was chosen as the “Most Innovative Development Company” in theNew Economy 2010 Pharmaceutical & Heathe 2011 Gold Leaf Award as the Early Stage Company of the Year (Health) from BIOTECanada.Gozes has published extensively in the fields of molecular neuroscience and neuroprotection (publications as cited PUBMED;of more than 15 patents and applications (Gozes as an applicant or inventor, includingcompound.

Professor Gozes received awas a Weizmann Postdoctoral Fellow at Massachusetts Institute of Technology, ResearchAssociate/Visiting Scientist at the Salk Institute and the Scripps Clinic and Research Foundation, a SeniorScientist/Associate Pat the National Institutes of Health (USA).

The Discovery and Preclinical Progress of the Neuroprotective Peptide,Treatment of Tauopathies

Illana

The Adams Super Center for Brain Studies; The Lily and Avraham Gildor Chair for the Investigation ofGrowth Factors; Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine,Tel Aviv*Allon Therapeutics Inc.

Davunetide (NAP=NAPVSIPQ), a peptide derived from activityis a neuroprotective drug candidate (CNS Drug Rev. 2005; 11:353).neurotrophic factor (ADNF) are potent neuroprotective proteins secreted from glial cells in response tovasoactive intestinal peptide (VIP) stimulation that protect neurons against death induced by electricalblockade. ADNF wasmedium and NAP (davunetide) was discovered by structuralADNF (J Mol Neurosci. 2000 14:61). Assessment of NAP (davunetide) a(SALLRSIPA) neuroprotection in primary cortical neuro


Illana Gozes, PhD


Dr. Gozes is the scientific founder, Chief Scientific Officer of Allon Therapeutics, where she serves as amember of the Board of Directors. Allon was chosen as the “Most Innovative Development Company” in theNew Economy 2010 Pharmaceutical & Heathe 2011 Gold Leaf Award as the Early Stage Company of the Year (Health) from BIOTECanada.Gozes has published extensively in the fields of molecular neuroscience and neuroprotection (publications as cited PUBMED;of more than 15 patents and applications (Gozes as an applicant or inventor, includingcompound.) Professor Gozes mentored

Professor Gozes received awas a Weizmann Postdoctoral Fellow at Massachusetts Institute of Technology, ResearchAssociate/Visiting Scientist at the Salk Institute and the Scripps Clinic and Research Foundation, a SeniorScientist/Associate Pat the National Institutes of Health (USA).


Illana Gozes*, Anat Idan

The Adams Super Center for Brain Studies; The Lily and Avraham Gildor Chair for the Investigation ofGrowth Factors; Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine,Tel Aviv University, Tel Aviv, Israel*Allon Therapeutics Inc.

Davunetide (NAP=NAPVSIPQ), a peptide derived from activityis a neuroprotective drug candidate (CNS Drug Rev. 2005; 11:353).neurotrophic factor (ADNF) are potent neuroprotective proteins secreted from glial cells in response tovasoactive intestinal peptide (VIP) stimulation that protect neurons against death induced by electricalblockade. ADNF wasmedium and NAP (davunetide) was discovered by structuralADNF (J Mol Neurosci. 2000 14:61). Assessment of NAP (davunetide) a(SALLRSIPA) neuroprotection in primary cortical neuro


Illana Gozes, PhD,

Dr. Gozes is a Professor of Clinical Biochemistry, the Lily and Avraham Gildor Chair forthe Investigation of Growth factors at Tel Aviv University (TAU) Sackler Faculty ofMedicine, where she heads the Dr. Diana and Zelman Elton (Elbaum) Laboratory forMolecular Neuroendocrinology. Professor Gozes serves as the Director of the AdamsSuper Center for Brain Studies at Tel Aviv University and the LevieInstitute for Functional Brain Imaging, a collaborative project between Tel Aviv Universityand the Sourasky Medical Center. Professor Gozes serves or has served as a member(or chair) of several faculty/university/national and international committees including


Dr. Gozes is the scientific founder, Chief Scientific Officer of Allon Therapeutics, where she serves as amember of the Board of Directors. Allon was chosen as the “Most Innovative Development Company” in theNew Economy 2010 Pharmaceutical & Heathe 2011 Gold Leaf Award as the Early Stage Company of the Year (Health) from BIOTECanada.Gozes has published extensively in the fields of molecular neuroscience and neuroprotection (publications as cited PUBMED;of more than 15 patents and applications (Gozes as an applicant or inventor, including

Professor Gozes mentored

Professor Gozes received awas a Weizmann Postdoctoral Fellow at Massachusetts Institute of Technology, ResearchAssociate/Visiting Scientist at the Salk Institute and the Scripps Clinic and Research Foundation, a SeniorScientist/Associate Professor at the Weizmann Institute and a distinguished Fogartyat the National Institutes of Health (USA).


Gozes*, Anat Idan-

The Adams Super Center for Brain Studies; The Lily and Avraham Gildor Chair for the Investigation ofGrowth Factors; Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine,

University, Tel Aviv, Israel*Allon Therapeutics Inc.,

Davunetide (NAP=NAPVSIPQ), a peptide derived from activityis a neuroprotective drug candidate (CNS Drug Rev. 2005; 11:353).neurotrophic factor (ADNF) are potent neuroprotective proteins secreted from glial cells in response tovasoactive intestinal peptide (VIP) stimulation that protect neurons against death induced by electricalblockade. ADNF was biochemically isolated (size and charge fractionations) from glial VIPmedium and NAP (davunetide) was discovered by structuralADNF (J Mol Neurosci. 2000 14:61). Assessment of NAP (davunetide) a(SALLRSIPA) neuroprotection in primary cortical neuro


Allon Therapeutics

Gozes is a Professor of Clinical Biochemistry, the Lily and Avraham Gildor Chair forthe Investigation of Growth factors at Tel Aviv University (TAU) Sackler Faculty ofMedicine, where she heads the Dr. Diana and Zelman Elton (Elbaum) Laboratory forMolecular Neuroendocrinology. Professor Gozes serves as the Director of the AdamsSuper Center for Brain Studies at Tel Aviv University and the Levie

te for Functional Brain Imaging, a collaborative project between Tel Aviv Universityand the Sourasky Medical Center. Professor Gozes serves or has served as a member(or chair) of several faculty/university/national and international committees including


Dr. Gozes is the scientific founder, Chief Scientific Officer of Allon Therapeutics, where she serves as amember of the Board of Directors. Allon was chosen as the “Most Innovative Development Company” in theNew Economy 2010 Pharmaceutical & Heathe 2011 Gold Leaf Award as the Early Stage Company of the Year (Health) from BIOTECanada.Gozes has published extensively in the fields of molecular neuroscience and neuroprotection (publications as cited PUBMED; overof more than 15 patents and applications (Gozes as an applicant or inventor, including

Professor Gozes mentored

Professor Gozes received a BSc from Tel Aviv University, awas a Weizmann Postdoctoral Fellow at Massachusetts Institute of Technology, ResearchAssociate/Visiting Scientist at the Salk Institute and the Scripps Clinic and Research Foundation, a Senior

rofessor at the Weizmann Institute and a distinguished Fogartyat the National Institutes of Health (USA).


-Feldman, Yan Jouroukhin


University, Tel Aviv, IsraelVancouver, BC

Davunetide (NAP=NAPVSIPQ), a peptide derived from activityis a neuroprotective drug candidate (CNS Drug Rev. 2005; 11:353).neurotrophic factor (ADNF) are potent neuroprotective proteins secreted from glial cells in response tovasoactive intestinal peptide (VIP) stimulation that protect neurons against death induced by electrical

biochemically isolated (size and charge fractionations) from glial VIPmedium and NAP (davunetide) was discovered by structuralADNF (J Mol Neurosci. 2000 14:61). Assessment of NAP (davunetide) a(SALLRSIPA) neuroprotection in primary cortical neuro

Therapeutics



serving now as a member of the Board of Governors of Tel Aviv University, the Tel Aviv University Senate,the Scientific Review Board of the Alzheimer’s Drug Discovery Foundation (New York, USA), the ScientificReview Board of the Rett Foundation, member of several Editorial Boards (Peptides, American Journal ofAlzheimer’s Research and other Dementias, Peptides Research and Therapeutics, Pharmaceutical DrugDesign) and Past President of the Israel Society for Neuroscience.of the Journal of Molecular Neuroscience, the Secretary General of the European Neuropeptide Club andthe Chair of the Summer Neuropeptide Conference, The International Advisory Committee of VIP PACAPand Related Peptides and Chair of the 2011 Conf

Dr. Gozes is the scientific founder, Chief Scientific Officer of Allon Therapeutics, where she serves as amember of the Board of Directors. Allon was chosen as the “Most Innovative Development Company” in theNew Economy 2010 Pharmaceutical & Healthcare Awards sponsored by New Economy Magazine and wonthe 2011 Gold Leaf Award as the Early Stage Company of the Year (Health) from BIOTECanada.Gozes has published extensively in the fields of molecular neuroscience and neuroprotection (

over 280 including a book, book chapters and reviews). She is coof more than 15 patents and applications (with more thanGozes as an applicant or inventor, including the composition of matter patent on davunetide, Allon's lead

Professor Gozes mentored more than

from Tel Aviv University, awas a Weizmann Postdoctoral Fellow at Massachusetts Institute of Technology, ResearchAssociate/Visiting Scientist at the Salk Institute and the Scripps Clinic and Research Foundation, a Senior

rofessor at the Weizmann Institute and a distinguished Fogartyat the National Institutes of Health (USA).

The Discovery and Preclinical Progress of the Neuroprotective Peptide,

Yan Jouroukhin


Vancouver, BC, Canada


biochemically isolated (size and charge fractionations) from glial VIPmedium and NAP (davunetide) was discovered by structuralADNF (J Mol Neurosci. 2000 14:61). Assessment of NAP (davunetide) a(SALLRSIPA) neuroprotection in primary cortical neuro

Therapeutics Inc.



serving now as a member of the Board of Governors of Tel Aviv University, the Tel Aviv University Senate,the Scientific Review Board of the Alzheimer’s Drug Discovery Foundation (New York, USA), the Scientific

of several Editorial Boards (Peptides, American Journal ofAlzheimer’s Research and other Dementias, Peptides Research and Therapeutics, Pharmaceutical DrugDesign) and Past President of the Israel Society for Neuroscience.of the Journal of Molecular Neuroscience, the Secretary General of the European Neuropeptide Club andthe Chair of the Summer Neuropeptide Conference, The International Advisory Committee of VIP PACAPand Related Peptides and Chair of the 2011 Conference.

Dr. Gozes is the scientific founder, Chief Scientific Officer of Allon Therapeutics, where she serves as amember of the Board of Directors. Allon was chosen as the “Most Innovative Development Company” in the

lthcare Awards sponsored by New Economy Magazine and wonthe 2011 Gold Leaf Award as the Early Stage Company of the Year (Health) from BIOTECanada.Gozes has published extensively in the fields of molecular neuroscience and neuroprotection (

280 including a book, book chapters and reviews). She is cowith more than 125 results found in the Worldwide data base for

the composition of matter patent on davunetide, Allon's leadmore than 50 students toward successful MSc and

from Tel Aviv University, awas a Weizmann Postdoctoral Fellow at Massachusetts Institute of Technology, ResearchAssociate/Visiting Scientist at the Salk Institute and the Scripps Clinic and Research Foundation, a Senior

rofessor at the Weizmann Institute and a distinguished Fogarty


Yan Jouroukhin


Canada


biochemically isolated (size and charge fractionations) from glial VIPmedium and NAP (davunetide) was discovered by structuralADNF (J Mol Neurosci. 2000 14:61). Assessment of NAP (davunetide) a(SALLRSIPA) neuroprotection in primary cortical neuro-glial cultures treated with amyloid beta showed that




of several Editorial Boards (Peptides, American Journal ofAlzheimer’s Research and other Dementias, Peptides Research and Therapeutics, Pharmaceutical DrugDesign) and Past President of the Israel Society for Neuroscience. Professor Gozes is the Editorof the Journal of Molecular Neuroscience, the Secretary General of the European Neuropeptide Club andthe Chair of the Summer Neuropeptide Conference, The International Advisory Committee of VIP PACAP



280 including a book, book chapters and reviews). She is co125 results found in the Worldwide data base for

the composition of matter patent on davunetide, Allon's lead50 students toward successful MSc and

from Tel Aviv University, a PhD from The Weizmann Institute of Science,was a Weizmann Postdoctoral Fellow at Massachusetts Institute of Technology, ResearchAssociate/Visiting Scientist at the Salk Institute and the Scripps Clinic and Research Foundation, a Senior




Davunetide (NAP=NAPVSIPQ), a peptide derived from activity-dependent neuroprotective protein (ADNP),is a neuroprotective drug candidate (CNS Drug Rev. 2005; 11:353).neurotrophic factor (ADNF) are potent neuroprotective proteins secreted from glial cells in response tovasoactive intestinal peptide (VIP) stimulation that protect neurons against death induced by electrical

biochemically isolated (size and charge fractionations) from glial VIPmedium and NAP (davunetide) was discovered by structural-functional similarity to a similar moiety withinADNF (J Mol Neurosci. 2000 14:61). Assessment of NAP (davunetide) a

glial cultures treated with amyloid beta showed that




of several Editorial Boards (Peptides, American Journal ofAlzheimer’s Research and other Dementias, Peptides Research and Therapeutics, Pharmaceutical Drug

Professor Gozes is the Editorof the Journal of Molecular Neuroscience, the Secretary General of the European Neuropeptide Club andthe Chair of the Summer Neuropeptide Conference, The International Advisory Committee of VIP PACAP




the composition of matter patent on davunetide, Allon's lead50 students toward successful MSc and

from The Weizmann Institute of Science,was a Weizmann Postdoctoral Fellow at Massachusetts Institute of Technology, ResearchAssociate/Visiting Scientist at the Salk Institute and the Scripps Clinic and Research Foundation, a Senior


The Discovery and Preclinical Progress of the Neuroprotective Peptide, davunetide


dependent neuroprotective protein (ADNP),is a neuroprotective drug candidate (CNS Drug Rev. 2005; 11:353). ADNP and activityneurotrophic factor (ADNF) are potent neuroprotective proteins secreted from glial cells in response tovasoactive intestinal peptide (VIP) stimulation that protect neurons against death induced by electrical

biochemically isolated (size and charge fractionations) from glial VIPfunctional similarity to a similar moiety within

ADNF (J Mol Neurosci. 2000 14:61). Assessment of NAP (davunetide) and all Dglial cultures treated with amyloid beta showed that

Gozes is a Professor of Clinical Biochemistry, the Lily and Avraham Gildor Chair forthe Investigation of Growth factors at Tel Aviv University (TAU) Sackler Faculty ofMedicine, where she heads the Dr. Diana and Zelman Elton (Elbaum) Laboratory forMolecular Neuroendocrinology. Professor Gozes serves as the Director of the AdamsSuper Center for Brain Studies at Tel Aviv University and the Levie-Edersheim




Professor Gozes is the Editorof the Journal of Molecular Neuroscience, the Secretary General of the European Neuropeptide Club andthe Chair of the Summer Neuropeptide Conference, The International Advisory Committee of VIP PACAP




the composition of matter patent on davunetide, Allon's lead50 students toward successful MSc and PhD


rofessor at the Weizmann Institute and a distinguished Fogarty-Scholar-in

davunetide, in the


dependent neuroprotective protein (ADNP),ADNP and activity

neurotrophic factor (ADNF) are potent neuroprotective proteins secreted from glial cells in response tovasoactive intestinal peptide (VIP) stimulation that protect neurons against death induced by electrical

biochemically isolated (size and charge fractionations) from glial VIP-functional similarity to a similar moiety within

nd all D-amino acid ADNFglial cultures treated with amyloid beta showed that

19

Gozes is a Professor of Clinical Biochemistry, the Lily and Avraham Gildor Chair forthe Investigation of Growth factors at Tel Aviv University (TAU) Sackler Faculty ofMedicine, where she heads the Dr. Diana and Zelman Elton (Elbaum) Laboratory forMolecular Neuroendocrinology. Professor Gozes serves as the Director of the Adams

Edersheim-Gitterte for Functional Brain Imaging, a collaborative project between Tel Aviv University

and the Sourasky Medical Center. Professor Gozes serves or has served as a member(or chair) of several faculty/university/national and international committees including



Professor Gozes is the Editor-in-Chiefof the Journal of Molecular Neuroscience, the Secretary General of the European Neuropeptide Club andthe Chair of the Summer Neuropeptide Conference, The International Advisory Committee of VIP PACAP


lthcare Awards sponsored by New Economy Magazine and wonthe 2011 Gold Leaf Award as the Early Stage Company of the Year (Health) from BIOTECanada. Prof.Gozes has published extensively in the fields of molecular neuroscience and neuroprotection (over 230

280 including a book, book chapters and reviews). She is co-inventor125 results found in the Worldwide data base for

the composition of matter patent on davunetide, Allon's leadPhD degrees.


in-Residence

, in the


dependent neuroprotective protein (ADNP),ADNP and activity-dependent


-conditionedfunctional similarity to a similar moiety within

amino acid ADNF-9glial cultures treated with amyloid beta showed that

Gozes is a Professor of Clinical Biochemistry, the Lily and Avraham Gildor Chair forthe Investigation of Growth factors at Tel Aviv University (TAU) Sackler Faculty ofMedicine, where she heads the Dr. Diana and Zelman Elton (Elbaum) Laboratory forMolecular Neuroendocrinology. Professor Gozes serves as the Director of the Adams

Gitterte for Functional Brain Imaging, a collaborative project between Tel Aviv University

and the Sourasky Medical Center. Professor Gozes serves or has served as a member(or chair) of several faculty/university/national and international committees including



Chiefof the Journal of Molecular Neuroscience, the Secretary General of the European Neuropeptide Club andthe Chair of the Summer Neuropeptide Conference, The International Advisory Committee of VIP PACAP


lthcare Awards sponsored by New Economy Magazine and wonProf.230

inventor125 results found in the Worldwide data base for

the composition of matter patent on davunetide, Allon's lead


Residence


dependent neuroprotective protein (ADNP),dependent


conditionedfunctional similarity to a similar moiety within

9glial cultures treated with amyloid beta showed that

20

both peptides reduced toxin-related neuronal damage and tau hyperphosphorylation (Curr Pharm Des.2011 Jul 5. [Epub ahead of print]). Studies in neuron-enriched cultures subjected to ischemia suggestedthat the effects on tau hyperphosphorylation were coupled to caspase 3 activation. Studies in a rat modelof cognitive impairment associated with diabetes showed in vivo protection against glial apoptosis coupledwith synaptic protection (synaptophysin). Furthermore, T2 magnetic resonance imaging revealed atrophy inthe prefrontal cortex of the diabetes rat group, which was prevented by davunetide (NAP) treatment andparalleled protection against impairment of spatial memory (Neurobiology of Disease, 2011, in press).Further, in a model of amyotrophic lateral sclerosis, davunetide (NAP) treatment protected against braindamage as detected by T2 and diffusion tensor imaging (DTI). Davunetide is currently being tested in aPhase II/III clinical trial assessing safety and efficacy in patients with progressive supranuclear palsy (AllonTherapeutics Inc., Trial identifier NCT01110720), a sporadic neurodegenerative disorder characterized byextensive tau pathology.

Support: Allon Therapeutics Inc., AMN Foundation, CFTAU/Montreal Circle of Friends.


Chad Dickey, PhD

hereditary dementia. He is currently funded through the NIH, the AlDrug Discovery Foundation and CurePSP for his research related to molecular mechanisms of Alzheimer’sdisease and tauopathies.

Modulating the Hsp70/DnaJ Protein Interface to Dictate Triage Decisions for Tau

Jose F

University of South Florida, Tampa

Accumulation of the microtubule associated protein tau inflicts neuronal death and memory loss associatedwith Alzheimer’s disease (AD). Tau also accumulates in more thancollectively termed tauopathies. Therefore tau is a tractable therapeutic target for AD and many otherdisorders. The chaperone family of proteins, and in particular the heat shock protein 70 (Hsp70) family, iscriticalassociated with granulovacular degenerating bodies (GVDs), which are major tauentities in AD neurons that are linked to autophagic clealso shown that Hsp70 associates with accumulated tau in the brain. However, the actual mechanismsinvolving Hsp70 with tau biology have been challenging to define. It has been shown that Hsp70 can eitherprobecoming clear. Hsp70 acts to seek out, identify and hold onto tau, but other chaperones termed DnaJproteins by manipulating substrate selection and Hsp70 Atau should be preserved, sequestered or destroyed. Thus, new evidence is emerging that will define themost therapeutically relevant chaperone targets for the treatment of AD.


Chad Dickey, PhD



Jose F. Abisambra, Umesh K. Jinwal, Chad A. Dickey


Accumulation of the microtubule associated protein tau inflicts neuronal death and memory loss associatedwith Alzheimer’s disease (AD). Tau also accumulates in more thancollectively termed tauopathies. Therefore tau is a tractable therapeutic target for AD and many otherdisorders. The chaperone family of proteins, and in particular the heat shock protein 70 (Hsp70) family, iscritical for tau processing. Indeed, the major cytosolic variant of the Hsp70 family, Hsp73, is stronglyassociated with granulovacular degenerating bodies (GVDs), which are major tauentities in AD neurons that are linked to autophagic clealso shown that Hsp70 associates with accumulated tau in the brain. However, the actual mechanismsinvolving Hsp70 with tau biology have been challenging to define. It has been shown that Hsp70 can eitherpromote tau clearance or functionally preserve it. The reason for this dichotomy, however, is finallybecoming clear. Hsp70 acts to seek out, identify and hold onto tau, but other chaperones termed DnaJproteins by manipulating substrate selection and Hsp70 Atau should be preserved, sequestered or destroyed. Thus, new evidence is emerging that will define themost therapeutically relevant chaperone targets for the treatment of AD.


Chad Dickey, PhD,

Dr. Chad Dickey joined the faculty at the Byrd Alzheimer’s Institute in September 2008. Dr.Dickey earned his PhD from the University of South Florida under the direction of Dr.David Morgan in 2004. His postJacksonville under the direction of Dr. Michael Hutton, an expert in the field of Alzheimer’sdisease genetics. He was a recipient of a New Investigator Award from the Alzheimer’sAssociation and a Rosalinde and Arthur Gilbert Foundation/AFAR New Investiin Alzheimer's Disease. Dr. Dickey has conducted two research projects for the Society forProgressive Supranuclear Palsy to study the mechanisms behind this particular form of



. Abisambra, Umesh K. Jinwal, Chad A. Dickey


Accumulation of the microtubule associated protein tau inflicts neuronal death and memory loss associatedwith Alzheimer’s disease (AD). Tau also accumulates in more thancollectively termed tauopathies. Therefore tau is a tractable therapeutic target for AD and many otherdisorders. The chaperone family of proteins, and in particular the heat shock protein 70 (Hsp70) family, is

for tau processing. Indeed, the major cytosolic variant of the Hsp70 family, Hsp73, is stronglyassociated with granulovacular degenerating bodies (GVDs), which are major tauentities in AD neurons that are linked to autophagic clealso shown that Hsp70 associates with accumulated tau in the brain. However, the actual mechanismsinvolving Hsp70 with tau biology have been challenging to define. It has been shown that Hsp70 can either

mote tau clearance or functionally preserve it. The reason for this dichotomy, however, is finallybecoming clear. Hsp70 acts to seek out, identify and hold onto tau, but other chaperones termed DnaJproteins by manipulating substrate selection and Hsp70 Atau should be preserved, sequestered or destroyed. Thus, new evidence is emerging that will define themost therapeutically relevant chaperone targets for the treatment of AD.


, University of South Florida





University of South Florida, Tampa, FL




University of South Florida


hereditary dementia. He is currently funded through the NIH, the AlDrug Discovery Foundation and CurePSP for his research related to molecular mechanisms of Alzheimer’s



FL




University of South Florida

Dr. Chad Dickey joined the faculty at the Byrd Alzheimer’s Institute in September 2008. Dr.Dickey earned his PhD from the University of South Florida under the direction of Dr.David Morgan in 2004. His post-doctoral training was done at the Mayo Clinic iJacksonville under the direction of Dr. Michael Hutton, an expert in the field of Alzheimer’sdisease genetics. He was a recipient of a New Investigator Award from the Alzheimer’sAssociation and a Rosalinde and Arthur Gilbert Foundation/AFAR New Investiin Alzheimer's Disease. Dr. Dickey has conducted two research projects for the Society forProgressive Supranuclear Palsy to study the mechanisms behind this particular form of

hereditary dementia. He is currently funded through the NIH, the AlDrug Discovery Foundation and CurePSP for his research related to molecular mechanisms of Alzheimer’s




for tau processing. Indeed, the major cytosolic variant of the Hsp70 family, Hsp73, is stronglyassociated with granulovacular degenerating bodies (GVDs), which are major tauentities in AD neurons that are linked to autophagic clearance mechanisms. Coalso shown that Hsp70 associates with accumulated tau in the brain. However, the actual mechanismsinvolving Hsp70 with tau biology have been challenging to define. It has been shown that Hsp70 can either

mote tau clearance or functionally preserve it. The reason for this dichotomy, however, is finallybecoming clear. Hsp70 acts to seek out, identify and hold onto tau, but other chaperones termed DnaJproteins by manipulating substrate selection and Hsp70 ATPase activity dictate whether this Hsp70 boundtau should be preserved, sequestered or destroyed. Thus, new evidence is emerging that will define themost therapeutically relevant chaperone targets for the treatment of AD.

Dr. Chad Dickey joined the faculty at the Byrd Alzheimer’s Institute in September 2008. Dr.Dickey earned his PhD from the University of South Florida under the direction of Dr.

doctoral training was done at the Mayo Clinic iJacksonville under the direction of Dr. Michael Hutton, an expert in the field of Alzheimer’sdisease genetics. He was a recipient of a New Investigator Award from the Alzheimer’sAssociation and a Rosalinde and Arthur Gilbert Foundation/AFAR New Investiin Alzheimer's Disease. Dr. Dickey has conducted two research projects for the Society forProgressive Supranuclear Palsy to study the mechanisms behind this particular form of

hereditary dementia. He is currently funded through the NIH, the Alzheimer’s Association, the Alzheimer’sDrug Discovery Foundation and CurePSP for his research related to molecular mechanisms of Alzheimer’s


Accumulation of the microtubule associated protein tau inflicts neuronal death and memory loss associatedwith Alzheimer’s disease (AD). Tau also accumulates in more than 15 other neurodegenerative diseasescollectively termed tauopathies. Therefore tau is a tractable therapeutic target for AD and many otherdisorders. The chaperone family of proteins, and in particular the heat shock protein 70 (Hsp70) family, is

for tau processing. Indeed, the major cytosolic variant of the Hsp70 family, Hsp73, is stronglyassociated with granulovacular degenerating bodies (GVDs), which are major tau

arance mechanisms. Coalso shown that Hsp70 associates with accumulated tau in the brain. However, the actual mechanismsinvolving Hsp70 with tau biology have been challenging to define. It has been shown that Hsp70 can either

mote tau clearance or functionally preserve it. The reason for this dichotomy, however, is finallybecoming clear. Hsp70 acts to seek out, identify and hold onto tau, but other chaperones termed DnaJ

TPase activity dictate whether this Hsp70 boundtau should be preserved, sequestered or destroyed. Thus, new evidence is emerging that will define themost therapeutically relevant chaperone targets for the treatment of AD.


doctoral training was done at the Mayo Clinic iJacksonville under the direction of Dr. Michael Hutton, an expert in the field of Alzheimer’sdisease genetics. He was a recipient of a New Investigator Award from the Alzheimer’sAssociation and a Rosalinde and Arthur Gilbert Foundation/AFAR New Investiin Alzheimer's Disease. Dr. Dickey has conducted two research projects for the Society forProgressive Supranuclear Palsy to study the mechanisms behind this particular form of

zheimer’s Association, the Alzheimer’sDrug Discovery Foundation and CurePSP for his research related to molecular mechanisms of Alzheimer’s


Accumulation of the microtubule associated protein tau inflicts neuronal death and memory loss associated15 other neurodegenerative diseases

collectively termed tauopathies. Therefore tau is a tractable therapeutic target for AD and many otherdisorders. The chaperone family of proteins, and in particular the heat shock protein 70 (Hsp70) family, is

for tau processing. Indeed, the major cytosolic variant of the Hsp70 family, Hsp73, is stronglyassociated with granulovacular degenerating bodies (GVDs), which are major tau-associated pathological

arance mechanisms. Co-localization studies havealso shown that Hsp70 associates with accumulated tau in the brain. However, the actual mechanismsinvolving Hsp70 with tau biology have been challenging to define. It has been shown that Hsp70 can either




doctoral training was done at the Mayo Clinic iJacksonville under the direction of Dr. Michael Hutton, an expert in the field of Alzheimer’sdisease genetics. He was a recipient of a New Investigator Award from the Alzheimer’sAssociation and a Rosalinde and Arthur Gilbert Foundation/AFAR New Investigator Awardin Alzheimer's Disease. Dr. Dickey has conducted two research projects for the Society forProgressive Supranuclear Palsy to study the mechanisms behind this particular form of





for tau processing. Indeed, the major cytosolic variant of the Hsp70 family, Hsp73, is stronglyassociated pathological

localization studies havealso shown that Hsp70 associates with accumulated tau in the brain. However, the actual mechanismsinvolving Hsp70 with tau biology have been challenging to define. It has been shown that Hsp70 can either



21


doctoral training was done at the Mayo Clinic inJacksonville under the direction of Dr. Michael Hutton, an expert in the field of Alzheimer’sdisease genetics. He was a recipient of a New Investigator Award from the Alzheimer’s

gator Awardin Alzheimer's Disease. Dr. Dickey has conducted two research projects for the Society forProgressive Supranuclear Palsy to study the mechanisms behind this particular form of









nJacksonville under the direction of Dr. Michael Hutton, an expert in the field of Alzheimer’sdisease genetics. He was a recipient of a New Investigator Award from the Alzheimer’s

gator Awardin Alzheimer's Disease. Dr. Dickey has conducted two research projects for the Society forProgressive Supranuclear Palsy to study the mechanisms behind this particular form of







TPase activity dictate whether this Hsp70 boundtau should be preserved, sequestered or destroyed. Thus, new evidence is emerging that will define the

22

Jeff Kuret

Chemistry and Current Alzheimer Research. Dr. Kuret’s laboratorand neurofibrillary lesion formation in Alzheimer’s disease and frontotemporal lobar degeneration.

Developing a Tau Imaging Agent for Alzheimer’s Disease

Jeff Kuret

The Ohio State University College of Medicine

Current methods for wholecompounds to aggregated forms of thetauFirst, neurofibrillary lesions appear at certain sites of predilection decades before the onset of dementia,potentially providing the means to detect disease at very early stages. Second,aggregate load correlates with neurodegeneration and cognitive decline in AD, providing a potentialsurrogate marker for disease. Because of the welland spatial distributionof drug treatments over time. Finally, neurofibrillary lesions are found in chronic traumatic encephalopathyand certain forms of frontotemporal lobar degeneration. Thudiagnosis of dementing illnesses that are difficult to distinguish based solely on clinical presentation andthat lack Ausing pharmacokinetic modeling methods, I will describe the molecular properties needed for detection ofneurofibrillary lesions in the presence of competing aggregates such as amyloid plaques. Second, usingbiochemical methods, I will describe the inteaggregates, and the role of amino acid side chains in imparting binding selectivity. Finally, throughpharmacological analysis, I will assess the feasibility of identifying probes with selectivity for tauA

Jeff Kuret



Jeff Kuret


Current methods for wholecompounds to aggregated forms of thetau-bearing neurofibrillary lesions couldFirst, neurofibrillary lesions appear at certain sites of predilection decades before the onset of dementia,potentially providing the means to detect disease at very early stages. Second,aggregate load correlates with neurodegeneration and cognitive decline in AD, providing a potentialsurrogate marker for disease. Because of the welland spatial distributionof drug treatments over time. Finally, neurofibrillary lesions are found in chronic traumatic encephalopathyand certain forms of frontotemporal lobar degeneration. Thudiagnosis of dementing illnesses that are difficult to distinguish based solely on clinical presentation andthat lack A lesions. Here I will summarize our progress in developing tauusing pharmacokinetic modeling methods, I will describe the molecular properties needed for detection ofneurofibrillary lesions in the presence of competing aggregates such as amyloid plaques. Second, usingbiochemical methods, I will describe the inteaggregates, and the role of amino acid side chains in imparting binding selectivity. Finally, throughpharmacological analysis, I will assess the feasibility of identifying probes with selectivity for tau.

Jeff Kuret, PhD, Ohio State

Dr. Kuret is a Professor of Molecular and Cellular Biochemistry at The Ohio StateUniversity. He completed his BS degree in biochemistry at the University of California,Los Angeles, and conducted graduate work with Professor Howard SchulmanUniversity. After earning his PhD degree in Pharmacology, he joined the laboratory of SirPhilip Cohen in the Medical Sciences Institute, Dundee, Scotland as a postdoctoral fellow,and served on the faculties of Cold Spring Harbor LaboratoryUniversity. He currently serves on the Drug Discovery (MNPSCenter for Scientific Review, and on the editorial boards of the Journal of Biological




Current methods for wholecompounds to aggregated forms of the

bearing neurofibrillary lesions couldFirst, neurofibrillary lesions appear at certain sites of predilection decades before the onset of dementia,potentially providing the means to detect disease at very early stages. Second,aggregate load correlates with neurodegeneration and cognitive decline in AD, providing a potentialsurrogate marker for disease. Because of the welland spatial distribution of neurofibrillary pathology, tauof drug treatments over time. Finally, neurofibrillary lesions are found in chronic traumatic encephalopathyand certain forms of frontotemporal lobar degeneration. Thudiagnosis of dementing illnesses that are difficult to distinguish based solely on clinical presentation and

lesions. Here I will summarize our progress in developing tauusing pharmacokinetic modeling methods, I will describe the molecular properties needed for detection ofneurofibrillary lesions in the presence of competing aggregates such as amyloid plaques. Second, usingbiochemical methods, I will describe the inteaggregates, and the role of amino acid side chains in imparting binding selectivity. Finally, throughpharmacological analysis, I will assess the feasibility of identifying probes with selectivity for tau

Ohio State University





Current methods for whole-brain imaging of dementia patients capture the binding of radiolabeledcompounds to aggregated forms of the

bearing neurofibrillary lesions couldFirst, neurofibrillary lesions appear at certain sites of predilection decades before the onset of dementia,potentially providing the means to detect disease at very early stages. Second,aggregate load correlates with neurodegeneration and cognitive decline in AD, providing a potentialsurrogate marker for disease. Because of the well

of neurofibrillary pathology, tauof drug treatments over time. Finally, neurofibrillary lesions are found in chronic traumatic encephalopathyand certain forms of frontotemporal lobar degeneration. Thudiagnosis of dementing illnesses that are difficult to distinguish based solely on clinical presentation and


University




The Ohio State University College of Medicine, Columbus, OH

brain imaging of dementia patients capture the binding of radiolabeledcompounds to aggregated forms of the -amyloid (A

bearing neurofibrillary lesions could complement the established AFirst, neurofibrillary lesions appear at certain sites of predilection decades before the onset of dementia,potentially providing the means to detect disease at very early stages. Second,aggregate load correlates with neurodegeneration and cognitive decline in AD, providing a potentialsurrogate marker for disease. Because of the well

of neurofibrillary pathology, tauof drug treatments over time. Finally, neurofibrillary lesions are found in chronic traumatic encephalopathyand certain forms of frontotemporal lobar degeneration. Thudiagnosis of dementing illnesses that are difficult to distinguish based solely on clinical presentation and


University




Columbus, OH

brain imaging of dementia patients capture the binding of radiolabeledamyloid (A) peptide. Development of selective radiotracers for

complement the established AFirst, neurofibrillary lesions appear at certain sites of predilection decades before the onset of dementia,potentially providing the means to detect disease at very early stages. Second,aggregate load correlates with neurodegeneration and cognitive decline in AD, providing a potentialsurrogate marker for disease. Because of the well-established relationship between disease progression

of neurofibrillary pathology, tau-based imaging could help monitor the effectivenessof drug treatments over time. Finally, neurofibrillary lesions are found in chronic traumatic encephalopathyand certain forms of frontotemporal lobar degeneration. Thudiagnosis of dementing illnesses that are difficult to distinguish based solely on clinical presentation and

lesions. Here I will summarize our progress in developing tauusing pharmacokinetic modeling methods, I will describe the molecular properties needed for detection ofneurofibrillary lesions in the presence of competing aggregates such as amyloid plaques. Second, usingbiochemical methods, I will describe the interactions between small molecules and crossaggregates, and the role of amino acid side chains in imparting binding selectivity. Finally, throughpharmacological analysis, I will assess the feasibility of identifying probes with selectivity for tau


Chemistry and Current Alzheimer Research. Dr. Kuret’s laboratory focuses primarily on tau aggregationand neurofibrillary lesion formation in Alzheimer’s disease and frontotemporal lobar degeneration.


Columbus, OH

brain imaging of dementia patients capture the binding of radiolabeled) peptide. Development of selective radiotracers for

complement the established AFirst, neurofibrillary lesions appear at certain sites of predilection decades before the onset of dementia,potentially providing the means to detect disease at very early stages. Second,aggregate load correlates with neurodegeneration and cognitive decline in AD, providing a potential

established relationship between disease progressionbased imaging could help monitor the effectiveness

of drug treatments over time. Finally, neurofibrillary lesions are found in chronic traumatic encephalopathyand certain forms of frontotemporal lobar degeneration. Thus tau-based imaging agents also may aid thediagnosis of dementing illnesses that are difficult to distinguish based solely on clinical presentation and

lesions. Here I will summarize our progress in developing tauusing pharmacokinetic modeling methods, I will describe the molecular properties needed for detection ofneurofibrillary lesions in the presence of competing aggregates such as amyloid plaques. Second, using

ractions between small molecules and crossaggregates, and the role of amino acid side chains in imparting binding selectivity. Finally, throughpharmacological analysis, I will assess the feasibility of identifying probes with selectivity for tau

Dr. Kuret is a Professor of Molecular and Cellular Biochemistry at The Ohio StateUniversity. He completed his BS degree in biochemistry at the University of California,Los Angeles, and conducted graduate work with Professor Howard SchulmanUniversity. After earning his PhD degree in Pharmacology, he joined the laboratory of SirPhilip Cohen in the Medical Sciences Institute, Dundee, Scotland as a postdoctoral fellow,and served on the faculties of Cold Spring Harbor LaboratoryUniversity. He currently serves on the Drug Discovery (MNPS-C) review panel at the NIHCenter for Scientific Review, and on the editorial boards of the Journal of Biological

y focuses primarily on tau aggregationand neurofibrillary lesion formation in Alzheimer’s disease and frontotemporal lobar degeneration.


imaging signature in several ways.First, neurofibrillary lesions appear at certain sites of predilection decades before the onset of dementia,potentially providing the means to detect disease at very early stages. Second, unlike Aaggregate load correlates with neurodegeneration and cognitive decline in AD, providing a potential


of drug treatments over time. Finally, neurofibrillary lesions are found in chronic traumatic encephalopathybased imaging agents also may aid the

diagnosis of dementing illnesses that are difficult to distinguish based solely on clinical presentation andlesions. Here I will summarize our progress in developing tau-based imaging agents. Firs

using pharmacokinetic modeling methods, I will describe the molecular properties needed for detection ofneurofibrillary lesions in the presence of competing aggregates such as amyloid plaques. Second, using


Dr. Kuret is a Professor of Molecular and Cellular Biochemistry at The Ohio StateUniversity. He completed his BS degree in biochemistry at the University of California,Los Angeles, and conducted graduate work with Professor Howard SchulmanUniversity. After earning his PhD degree in Pharmacology, he joined the laboratory of SirPhilip Cohen in the Medical Sciences Institute, Dundee, Scotland as a postdoctoral fellow,and served on the faculties of Cold Spring Harbor Laboratory and Northwestern

C) review panel at the NIHCenter for Scientific Review, and on the editorial boards of the Journal of Biological

y focuses primarily on tau aggregationand neurofibrillary lesion formation in Alzheimer’s disease and frontotemporal lobar degeneration.


imaging signature in several ways.First, neurofibrillary lesions appear at certain sites of predilection decades before the onset of dementia,

unlike A aggregates, tauaggregate load correlates with neurodegeneration and cognitive decline in AD, providing a potential



diagnosis of dementing illnesses that are difficult to distinguish based solely on clinical presentation andbased imaging agents. Firs



Dr. Kuret is a Professor of Molecular and Cellular Biochemistry at The Ohio StateUniversity. He completed his BS degree in biochemistry at the University of California,Los Angeles, and conducted graduate work with Professor Howard Schulman at StanfordUniversity. After earning his PhD degree in Pharmacology, he joined the laboratory of SirPhilip Cohen in the Medical Sciences Institute, Dundee, Scotland as a postdoctoral fellow,

and NorthwesternC) review panel at the NIH

Center for Scientific Review, and on the editorial boards of the Journal of Biologicaly focuses primarily on tau aggregation

and neurofibrillary lesion formation in Alzheimer’s disease and frontotemporal lobar degeneration.



aggregates, tauaggregate load correlates with neurodegeneration and cognitive decline in AD, providing a potential



diagnosis of dementing illnesses that are difficult to distinguish based solely on clinical presentation andbased imaging agents. First,


ractions between small molecules and cross--sheetaggregates, and the role of amino acid side chains in imparting binding selectivity. Finally, throughpharmacological analysis, I will assess the feasibility of identifying probes with selectivity for tau relative to

Dr. Kuret is a Professor of Molecular and Cellular Biochemistry at The Ohio StateUniversity. He completed his BS degree in biochemistry at the University of California,

at StanfordUniversity. After earning his PhD degree in Pharmacology, he joined the laboratory of SirPhilip Cohen in the Medical Sciences Institute, Dundee, Scotland as a postdoctoral fellow,

and NorthwesternC) review panel at the NIH

Center for Scientific Review, and on the editorial boards of the Journal of Biologicaly focuses primarily on tau aggregation



aggregates, tauaggregate load correlates with neurodegeneration and cognitive decline in AD, providing a potential



diagnosis of dementing illnesses that are difficult to distinguish based solely on clinical presentation andt,


sheetaggregates, and the role of amino acid side chains in imparting binding selectivity. Finally, through

relative to


Rakez Kayed

disorders, their structure, toxicity and role in the disease pathogenesis. We were able to engineerconformation specific mouse monoclonal antibodies against tau and amyloid oligomers. The antibodies wedeveloped do not recogneliminate the pathological oligomeric form of the protein. We use these antibodies and other reagents andmethods we developed to study neurodegenerative diseases in cell culpostmortem tissues.

These novel reagents have many applications, including vaccine development for treatment for AD andother tauopathies, early diagnosis and biomarkers, drug discovery and the design of new reagents that candecrease or eliminate tau and amyloid neurotoxicity.

Targeting Tau Oligomers through Immunotherapy

Rakez Kayed

University of Texas

Tau oligomers represent a neurotoxic entity that forms prior to NFTs and has emerged aspathogenic tau species in neurodegenerative tauopathies and a possible mediator of amyloidtoxicity in AD. Recent findings from animal models of tauopathies suggest that tau oligomers play a keyrole in eliciting behavioral impairments. WeThis antibody does not recognize the soluble functional tau or mature tau tangles and has a high affinity totau oligomers. We used TOMA to vaccinate two animal models the (JNPL3) overexpressingtau protein P301L and the Tg2576 overexpressing human APP with the Swedish mutation, in both modelssingle TOMA injection reversed the phenotypes. Biochemical and immunohistological analyses revealedthat the improvement coincides with reductP301L tau model. In the Tg2576 model the improvement coincides with the reduction of both tau and Aβ oligomers without affecting the plaques load, this novel finding indicate that the relation bettau is more complex than previously depicted.


Rakez Kayed

disorders, their structure, toxicity and role in the disease pathogenesis. We were able to engineerconformation specific mouse monoclonal antibodies against tau and amyloid oligomers. The antibodies wedeveloped do not recogneliminate the pathological oligomeric form of the protein. We use these antibodies and other reagents andmethods we developed to study neurodegenerative diseases in cell culpostmortem tissues.



Rakez Kayed

University of Texas



Rakez Kayed, PhD,

Assistant Professor at the Departments of Neurology and Cell Biology and Neuroscience,and a member of George & Cynthia Mitchell Center for Neurodegenerative Diseases atUniversity of

Dr. Kayed is a pioneer in the development of conformational antibodies and theirapplications, and has coauthored more than sixty articles in peer

Dr. Kayed`s research focuses on tau and amyloid odisorders, their structure, toxicity and role in the disease pathogenesis. We were able to engineerconformation specific mouse monoclonal antibodies against tau and amyloid oligomers. The antibodies wedeveloped do not recogneliminate the pathological oligomeric form of the protein. We use these antibodies and other reagents andmethods we developed to study neurodegenerative diseases in cell culpostmortem tissues.



Rakez Kayed

University of Texas Medical Branch



, PhD, University of Texas

Assistant Professor at the Departments of Neurology and Cell Biology and Neuroscience,and a member of George & Cynthia Mitchell Center for Neurodegenerative Diseases atUniversity of Texas Medical Branch, Galveston


Dr. Kayed`s research focuses on tau and amyloid odisorders, their structure, toxicity and role in the disease pathogenesis. We were able to engineerconformation specific mouse monoclonal antibodies against tau and amyloid oligomers. The antibodies wedeveloped do not recognize endogenous functional proteins e.g. monomeric tau; they specifically bind andeliminate the pathological oligomeric form of the protein. We use these antibodies and other reagents andmethods we developed to study neurodegenerative diseases in cell cul



Medical Branch, Galveston, TX


University of Texas

Assistant Professor at the Departments of Neurology and Cell Biology and Neuroscience,and a member of George & Cynthia Mitchell Center for Neurodegenerative Diseases at

Texas Medical Branch, Galveston


Dr. Kayed`s research focuses on tau and amyloid odisorders, their structure, toxicity and role in the disease pathogenesis. We were able to engineerconformation specific mouse monoclonal antibodies against tau and amyloid oligomers. The antibodies we

ize endogenous functional proteins e.g. monomeric tau; they specifically bind andeliminate the pathological oligomeric form of the protein. We use these antibodies and other reagents andmethods we developed to study neurodegenerative diseases in cell cul



, Galveston, TX

Tau oligomers represent a neurotoxic entity that forms prior to NFTs and has emerged aspathogenic tau species in neurodegenerative tauopathies and a possible mediator of amyloidtoxicity in AD. Recent findings from animal models of tauopathies suggest that tau oligomers play a keyrole in eliciting behavioral impairments. We developed a novel antiThis antibody does not recognize the soluble functional tau or mature tau tangles and has a high affinity totau oligomers. We used TOMA to vaccinate two animal models the (JNPL3) overexpressingtau protein P301L and the Tg2576 overexpressing human APP with the Swedish mutation, in both modelssingle TOMA injection reversed the phenotypes. Biochemical and immunohistological analyses revealedthat the improvement coincides with reduction of tau oligomers not NFTs or phosphoP301L tau model. In the Tg2576 model the improvement coincides with the reduction of both tau and Aβ oligomers without affecting the plaques load, this novel finding indicate that the relation bettau is more complex than previously depicted.

University of Texas Medical Branch


Texas Medical Branch, Galveston






, Galveston, TX

Tau oligomers represent a neurotoxic entity that forms prior to NFTs and has emerged aspathogenic tau species in neurodegenerative tauopathies and a possible mediator of amyloidtoxicity in AD. Recent findings from animal models of tauopathies suggest that tau oligomers play a key

developed a novel antiThis antibody does not recognize the soluble functional tau or mature tau tangles and has a high affinity totau oligomers. We used TOMA to vaccinate two animal models the (JNPL3) overexpressingtau protein P301L and the Tg2576 overexpressing human APP with the Swedish mutation, in both modelssingle TOMA injection reversed the phenotypes. Biochemical and immunohistological analyses revealed

ion of tau oligomers not NFTs or phosphoP301L tau model. In the Tg2576 model the improvement coincides with the reduction of both tau and Aβ oligomers without affecting the plaques load, this novel finding indicate that the relation bet

Medical Branch


Texas Medical Branch, Galveston, TX.




These novel reagents have many applications, including vaccine development for treatment for AD andother tauopathies, early diagnosis and biomarkers, drug discovery and the design of new reagents that can


developed a novel anti-tau oligomer specific antibody (TOMA).This antibody does not recognize the soluble functional tau or mature tau tangles and has a high affinity totau oligomers. We used TOMA to vaccinate two animal models the (JNPL3) overexpressingtau protein P301L and the Tg2576 overexpressing human APP with the Swedish mutation, in both modelssingle TOMA injection reversed the phenotypes. Biochemical and immunohistological analyses revealed



Dr. Kayed is a pioneer in the development of conformational antibodies and theirapplications, and has coauthored more than sixty articles in peer-reviewed journals.

Dr. Kayed`s research focuses on tau and amyloid oligomers in neurodegenerativedisorders, their structure, toxicity and role in the disease pathogenesis. We were able to engineerconformation specific mouse monoclonal antibodies against tau and amyloid oligomers. The antibodies we

ize endogenous functional proteins e.g. monomeric tau; they specifically bind andeliminate the pathological oligomeric form of the protein. We use these antibodies and other reagents andmethods we developed to study neurodegenerative diseases in cell cultures, animal models and



tau oligomer specific antibody (TOMA).This antibody does not recognize the soluble functional tau or mature tau tangles and has a high affinity totau oligomers. We used TOMA to vaccinate two animal models the (JNPL3) overexpressingtau protein P301L and the Tg2576 overexpressing human APP with the Swedish mutation, in both modelssingle TOMA injection reversed the phenotypes. Biochemical and immunohistological analyses revealed



Dr. Kayed is a pioneer in the development of conformational antibodies and theirreviewed journals.

ligomers in neurodegenerativedisorders, their structure, toxicity and role in the disease pathogenesis. We were able to engineerconformation specific mouse monoclonal antibodies against tau and amyloid oligomers. The antibodies we

ize endogenous functional proteins e.g. monomeric tau; they specifically bind andeliminate the pathological oligomeric form of the protein. We use these antibodies and other reagents and

tures, animal models and



tau oligomer specific antibody (TOMA).This antibody does not recognize the soluble functional tau or mature tau tangles and has a high affinity totau oligomers. We used TOMA to vaccinate two animal models the (JNPL3) overexpressing mutant humantau protein P301L and the Tg2576 overexpressing human APP with the Swedish mutation, in both modelssingle TOMA injection reversed the phenotypes. Biochemical and immunohistological analyses revealed

ion of tau oligomers not NFTs or phospho-tau species in theP301L tau model. In the Tg2576 model the improvement coincides with the reduction of both tau and Aβ oligomers without affecting the plaques load, this novel finding indicate that the relation between Aβ and

23


Dr. Kayed is a pioneer in the development of conformational antibodies and theirreviewed journals.





Tau oligomers represent a neurotoxic entity that forms prior to NFTs and has emerged as the truepathogenic tau species in neurodegenerative tauopathies and a possible mediator of amyloid-β (Aβ) toxicity in AD. Recent findings from animal models of tauopathies suggest that tau oligomers play a key

tau oligomer specific antibody (TOMA).This antibody does not recognize the soluble functional tau or mature tau tangles and has a high affinity to

mutant humantau protein P301L and the Tg2576 overexpressing human APP with the Swedish mutation, in both modelssingle TOMA injection reversed the phenotypes. Biochemical and immunohistological analyses revealed

tau species in theP301L tau model. In the Tg2576 model the improvement coincides with the reduction of both tau and Aβ

ween Aβ and


Dr. Kayed is a pioneer in the development of conformational antibodies and their





the trueβ (Aβ)

toxicity in AD. Recent findings from animal models of tauopathies suggest that tau oligomers play a keytau oligomer specific antibody (TOMA).

This antibody does not recognize the soluble functional tau or mature tau tangles and has a high affinity tomutant human

tau protein P301L and the Tg2576 overexpressing human APP with the Swedish mutation, in both modelssingle TOMA injection reversed the phenotypes. Biochemical and immunohistological analyses revealed

tau species in theP301L tau model. In the Tg2576 model the improvement coincides with the reduction of both tau and Aβ

ween Aβ and

24

Karen Duff

translational research program. She has been awarded several honors and awards including the PotamkinPrize in 2006.

In the last 20 years, Dr. Duff has genetically engineered mouse models for AD, tauopatsynucleinopathies. These mice have been used in a wide range of studies from MRI and PET fordiagnostics development, to proofin studying how AD related pathology and dysfApoE genotype in AD and the role of autophagy in tauopathies. Drreviewed research articles and she is a regular speaker at scientific meetings around the world. Her work ismainly funded by the NIH.

Tau Clearance by Autophagy

Karen Duff, Natura Myeku, Wai

Columbia Uni

Accumulation of abnormal protein aggregates is a hall mark of multiple neurodegenerative disordersincluding Alzheimer’s disease (AD), frontotemporal lobe dementia (FTD) and Parkinson’s disease (PD).Several approaches have beenmodulation of protein degradation. Multiple protein degradation pathways exist including ubiquitinproteasome system (UPS) mediated clearance which acts on smaller, misfolded proteins,(macroautophagy, microautophagy, and chaperone mediated autophagy) which acts on larger, misfoldedor aggregated proteins, and dysfunctional organelles. Controlled autophagy plays a crucial role in cellsurvival and in regulating multiple celneurodegenerative diseases due to failed clearance of diseasehave come to be recognized as an important, perhaps even necessary therapeutic targAlzheimer’s disease, work has accelerated to understand how tau changes from a normal, soluble, axonal,microtubulerelocated in the somatodendriticpathological forms of tau in the cell as the basis for therapeutic intervention. We have demonstrated thatmice with progressive tauopathy show a decline in proteasome function, and an inductionthe same time as fibrillar tau aggregates start to accumulate. Therapeutic approaches to upregulateautophagy using drugs such as the disaccharide trehalose or the phenothiazine Methylene Blue and theirimpact on tau pathology and functiona

Karen Duff





Columbia Uni

Accumulation of abnormal protein aggregates is a hall mark of multiple neurodegenerative disordersincluding Alzheimer’s disease (AD), frontotemporal lobe dementia (FTD) and Parkinson’s disease (PD).Several approaches have beenmodulation of protein degradation. Multiple protein degradation pathways exist including ubiquitinproteasome system (UPS) mediated clearance which acts on smaller, misfolded proteins,(macroautophagy, microautophagy, and chaperone mediated autophagy) which acts on larger, misfoldedor aggregated proteins, and dysfunctional organelles. Controlled autophagy plays a crucial role in cellsurvival and in regulating multiple celneurodegenerative diseases due to failed clearance of diseasehave come to be recognized as an important, perhaps even necessary therapeutic targAlzheimer’s disease, work has accelerated to understand how tau changes from a normal, soluble, axonal,microtubule-associated protein to a hyperphosphorylated, insoluble, cytosolic filamentous protein that hasrelocated in the somatodendriticpathological forms of tau in the cell as the basis for therapeutic intervention. We have demonstrated thatmice with progressive tauopathy show a decline in proteasome function, and an inductionthe same time as fibrillar tau aggregates start to accumulate. Therapeutic approaches to upregulateautophagy using drugs such as the disaccharide trehalose or the phenothiazine Methylene Blue and theirimpact on tau pathology and functiona

Karen Duff, PhD, Columbia University and N

Dr. Duff received her PhCambridge (UK) in 1991. FromAlison Goate, then from 1992an assistant professor position from 1994professor at Mayo Clinic, Jacksonviprofessor position, at the Nathan Kline Institute/ New York University, New York. Since2006 she has been a tenured professor at the Taub Institute at Columbia University, witha joint position at the New York





Columbia University, New York, NY

Accumulation of abnormal protein aggregates is a hall mark of multiple neurodegenerative disordersincluding Alzheimer’s disease (AD), frontotemporal lobe dementia (FTD) and Parkinson’s disease (PD).Several approaches have beenmodulation of protein degradation. Multiple protein degradation pathways exist including ubiquitinproteasome system (UPS) mediated clearance which acts on smaller, misfolded proteins,(macroautophagy, microautophagy, and chaperone mediated autophagy) which acts on larger, misfoldedor aggregated proteins, and dysfunctional organelles. Controlled autophagy plays a crucial role in cellsurvival and in regulating multiple celneurodegenerative diseases due to failed clearance of diseasehave come to be recognized as an important, perhaps even necessary therapeutic targAlzheimer’s disease, work has accelerated to understand how tau changes from a normal, soluble, axonal,

associated protein to a hyperphosphorylated, insoluble, cytosolic filamentous protein that hasrelocated in the somatodendriticpathological forms of tau in the cell as the basis for therapeutic intervention. We have demonstrated thatmice with progressive tauopathy show a decline in proteasome function, and an inductionthe same time as fibrillar tau aggregates start to accumulate. Therapeutic approaches to upregulateautophagy using drugs such as the disaccharide trehalose or the phenothiazine Methylene Blue and theirimpact on tau pathology and functiona

Columbia University and N

Dr. Duff received her PhCambridge (UK) in 1991. FromAlison Goate, then from 1992an assistant professor position from 1994professor at Mayo Clinic, Jacksonviprofessor position, at the Nathan Kline Institute/ New York University, New York. Since2006 she has been a tenured professor at the Taub Institute at Columbia University, witha joint position at the New York

translational research program. She has been awarded several honors and awards including the Potamkin

In the last 20 years, Dr. Duff has genetically engineered mouse models for AD, tauopatsynucleinopathies. These mice have been used in a wide range of studies from MRI and PET fordiagnostics development, to proof-ofin studying how AD related pathology and dysfApoE genotype in AD and the role of autophagy in tauopathies. Drreviewed research articles and she is a regular speaker at scientific meetings around the world. Her work ismainly funded by the NIH.


Karen Duff, Natura Myeku, Wai-Haung (Ho) Yu

, New York, NY

Accumulation of abnormal protein aggregates is a hall mark of multiple neurodegenerative disordersincluding Alzheimer’s disease (AD), frontotemporal lobe dementia (FTD) and Parkinson’s disease (PD).Several approaches have been proposed to reduce the levels of abnormal proteins in cells, includingmodulation of protein degradation. Multiple protein degradation pathways exist including ubiquitinproteasome system (UPS) mediated clearance which acts on smaller, misfolded proteins,(macroautophagy, microautophagy, and chaperone mediated autophagy) which acts on larger, misfoldedor aggregated proteins, and dysfunctional organelles. Controlled autophagy plays a crucial role in cellsurvival and in regulating multiple celneurodegenerative diseases due to failed clearance of diseasehave come to be recognized as an important, perhaps even necessary therapeutic targAlzheimer’s disease, work has accelerated to understand how tau changes from a normal, soluble, axonal,

associated protein to a hyperphosphorylated, insoluble, cytosolic filamentous protein that hasrelocated in the somatodendritic compartment. Considerable efforts are now underway to reducepathological forms of tau in the cell as the basis for therapeutic intervention. We have demonstrated thatmice with progressive tauopathy show a decline in proteasome function, and an inductionthe same time as fibrillar tau aggregates start to accumulate. Therapeutic approaches to upregulateautophagy using drugs such as the disaccharide trehalose or the phenothiazine Methylene Blue and theirimpact on tau pathology and functiona

Columbia University and N

Dr. Duff received her PhD from Sydney Brenner’s depCambridge (UK) in 1991. FromAlison Goate, then from 1992-1994 with John Hardy at USF Tampa, FL where she heldan assistant professor position from 1994professor at Mayo Clinic, Jacksonviprofessor position, at the Nathan Kline Institute/ New York University, New York. Since2006 she has been a tenured professor at the Taub Institute at Columbia University, witha joint position at the New York


In the last 20 years, Dr. Duff has genetically engineered mouse models for AD, tauopatsynucleinopathies. These mice have been used in a wide range of studies from MRI and PET for

of-concept testing of therapeutic targets. Currently, her main interest isin studying how AD related pathology and dysfunction propagates though the brain, the role of aging andApoE genotype in AD and the role of autophagy in tauopathies. Drreviewed research articles and she is a regular speaker at scientific meetings around the world. Her work is

Haung (Ho) Yu

Accumulation of abnormal protein aggregates is a hall mark of multiple neurodegenerative disordersincluding Alzheimer’s disease (AD), frontotemporal lobe dementia (FTD) and Parkinson’s disease (PD).

proposed to reduce the levels of abnormal proteins in cells, includingmodulation of protein degradation. Multiple protein degradation pathways exist including ubiquitinproteasome system (UPS) mediated clearance which acts on smaller, misfolded proteins,(macroautophagy, microautophagy, and chaperone mediated autophagy) which acts on larger, misfoldedor aggregated proteins, and dysfunctional organelles. Controlled autophagy plays a crucial role in cellsurvival and in regulating multiple cell functions but loss of control has been implicated in pathogenesis ofneurodegenerative diseases due to failed clearance of diseasehave come to be recognized as an important, perhaps even necessary therapeutic targAlzheimer’s disease, work has accelerated to understand how tau changes from a normal, soluble, axonal,

associated protein to a hyperphosphorylated, insoluble, cytosolic filamentous protein that hascompartment. Considerable efforts are now underway to reduce

pathological forms of tau in the cell as the basis for therapeutic intervention. We have demonstrated thatmice with progressive tauopathy show a decline in proteasome function, and an inductionthe same time as fibrillar tau aggregates start to accumulate. Therapeutic approaches to upregulateautophagy using drugs such as the disaccharide trehalose or the phenothiazine Methylene Blue and theirimpact on tau pathology and functional outcomes will be presented.

Columbia University and New York State Psychiatric Institute

D from Sydney Brenner’s depCambridge (UK) in 1991. From 1991-92 she undertook a post

1994 with John Hardy at USF Tampa, FL where she heldan assistant professor position from 1994professor at Mayo Clinic, Jacksonville, FL. From 1998professor position, at the Nathan Kline Institute/ New York University, New York. Since2006 she has been a tenured professor at the Taub Institute at Columbia University, witha joint position at the New York State Psychiatric Institute where she continues her



concept testing of therapeutic targets. Currently, her main interest isunction propagates though the brain, the role of aging and

ApoE genotype in AD and the role of autophagy in tauopathies. Drreviewed research articles and she is a regular speaker at scientific meetings around the world. Her work is


proposed to reduce the levels of abnormal proteins in cells, includingmodulation of protein degradation. Multiple protein degradation pathways exist including ubiquitinproteasome system (UPS) mediated clearance which acts on smaller, misfolded proteins,(macroautophagy, microautophagy, and chaperone mediated autophagy) which acts on larger, misfoldedor aggregated proteins, and dysfunctional organelles. Controlled autophagy plays a crucial role in cell

l functions but loss of control has been implicated in pathogenesis ofneurodegenerative diseases due to failed clearance of diseasehave come to be recognized as an important, perhaps even necessary therapeutic targAlzheimer’s disease, work has accelerated to understand how tau changes from a normal, soluble, axonal,


pathological forms of tau in the cell as the basis for therapeutic intervention. We have demonstrated thatmice with progressive tauopathy show a decline in proteasome function, and an inductionthe same time as fibrillar tau aggregates start to accumulate. Therapeutic approaches to upregulateautophagy using drugs such as the disaccharide trehalose or the phenothiazine Methylene Blue and their

l outcomes will be presented.

ew York State Psychiatric Institute

D from Sydney Brenner’s dep92 she undertook a post

1994 with John Hardy at USF Tampa, FL where she heldan assistant professor position from 1994-96. From 1996

lle, FL. From 1998professor position, at the Nathan Kline Institute/ New York University, New York. Since2006 she has been a tenured professor at the Taub Institute at Columbia University, with

State Psychiatric Institute where she continues hertranslational research program. She has been awarded several honors and awards including the Potamkin



ApoE genotype in AD and the role of autophagy in tauopathies. Dr.reviewed research articles and she is a regular speaker at scientific meetings around the world. Her work is



l functions but loss of control has been implicated in pathogenesis ofneurodegenerative diseases due to failed clearance of disease-associated proteins. As tau and tangleshave come to be recognized as an important, perhaps even necessary therapeutic targAlzheimer’s disease, work has accelerated to understand how tau changes from a normal, soluble, axonal,



l outcomes will be presented.


D from Sydney Brenner’s departmen92 she undertook a post-doc position in London with

1994 with John Hardy at USF Tampa, FL where she held96. From 1996-1998 she was an associate

lle, FL. From 1998-2006 she held an associateprofessor position, at the Nathan Kline Institute/ New York University, New York. Since2006 she has been a tenured professor at the Taub Institute at Columbia University, with




Duff’s CV includes over 110 peerreviewed research articles and she is a regular speaker at scientific meetings around the world. Her work is



l functions but loss of control has been implicated in pathogenesis ofassociated proteins. As tau and tangles

have come to be recognized as an important, perhaps even necessary therapeutic targAlzheimer’s disease, work has accelerated to understand how tau changes from a normal, soluble, axonal,




artment at the University ofdoc position in London with

1994 with John Hardy at USF Tampa, FL where she held1998 she was an associate

2006 she held an associateprofessor position, at the Nathan Kline Institute/ New York University, New York. Since2006 she has been a tenured professor at the Taub Institute at Columbia University, with






proposed to reduce the levels of abnormal proteins in cells, includingmodulation of protein degradation. Multiple protein degradation pathways exist including ubiquitinproteasome system (UPS) mediated clearance which acts on smaller, misfolded proteins, and autophagy(macroautophagy, microautophagy, and chaperone mediated autophagy) which acts on larger, misfoldedor aggregated proteins, and dysfunctional organelles. Controlled autophagy plays a crucial role in cell


have come to be recognized as an important, perhaps even necessary therapeutic targAlzheimer’s disease, work has accelerated to understand how tau changes from a normal, soluble, axonal,


pathological forms of tau in the cell as the basis for therapeutic intervention. We have demonstrated thatmice with progressive tauopathy show a decline in proteasome function, and an induction of autophagy atthe same time as fibrillar tau aggregates start to accumulate. Therapeutic approaches to upregulateautophagy using drugs such as the disaccharide trehalose or the phenothiazine Methylene Blue and their


t at the University ofdoc position in London with




In the last 20 years, Dr. Duff has genetically engineered mouse models for AD, tauopathies andsynucleinopathies. These mice have been used in a wide range of studies from MRI and PET for




proposed to reduce the levels of abnormal proteins in cells, includingmodulation of protein degradation. Multiple protein degradation pathways exist including ubiquitin-

and autophagy(macroautophagy, microautophagy, and chaperone mediated autophagy) which acts on larger, misfoldedor aggregated proteins, and dysfunctional organelles. Controlled autophagy plays a crucial role in cell


have come to be recognized as an important, perhaps even necessary therapeutic target to treatAlzheimer’s disease, work has accelerated to understand how tau changes from a normal, soluble, axonal,


pathological forms of tau in the cell as the basis for therapeutic intervention. We have demonstrated thatof autophagy at

the same time as fibrillar tau aggregates start to accumulate. Therapeutic approaches to upregulateautophagy using drugs such as the disaccharide trehalose or the phenothiazine Methylene Blue and their

t at the University ofdoc position in London with




hies andsynucleinopathies. These mice have been used in a wide range of studies from MRI and PET for




proposed to reduce the levels of abnormal proteins in cells, including

and autophagy(macroautophagy, microautophagy, and chaperone mediated autophagy) which acts on larger, misfoldedor aggregated proteins, and dysfunctional organelles. Controlled autophagy plays a crucial role in cell


et to treatAlzheimer’s disease, work has accelerated to understand how tau changes from a normal, soluble, axonal,


pathological forms of tau in the cell as the basis for therapeutic intervention. We have demonstrated thatof autophagy at

the same time as fibrillar tau aggregates start to accumulate. Therapeutic approaches to upregulateautophagy using drugs such as the disaccharide trehalose or the phenothiazine Methylene Blue and their


II. Inflammation, Chaperones and Novel TargetsChair: D. Martin Watterson, PhD, Northwestern University

Design and Refinement of Novel Small Molecule Compounds Targeting Proinflammatory CytokineOverproduction: A Potential Disease-Modifying Therapeutic Approach to CNS DiseasesD. Martin Watterson, PhD, Northwestern University

Optimizing New Drug Candidates for Protein Disulfide Isomerase, A Novel Target forNeurodegenerative DiseasesDonald C. Lo, PhD, Duke University Medical Center

Proof-of-Concept That Small Molecule Structure Correctors Are Capable of Abolishing theDetrimental Effects of Apolipoprotein E4 in Vitro by Inhibiting Domain InteractionRobert W. Mahley, MD, PhD, Gladstone Institute of Neurological Disease and University of California, SanFrancisco

Tau Lowering Agents for the Treatment of Alzheimer’s DiseaseAllen Reitz, PhD, ALS Biopharma, LLC

Modulation of Ganglioside Catabolism Using Pharmacological Chaperones: A Novel TherapeuticApproach for Alzheimer’s DiseaseBrandon Wustman, PhD, Amicus Therapeutics, Inc.

Heat Shock Protein 90 in Neurodegenerative DiseasesGabriela Chiosis, PhD, Memorial Sloan Kettering Cancer Center

26

D. Martin Watterson

At Northwestern, he has served as a Department Chair, CoDiscovery and Chemical Biology and a University Center, and founding director of the Drug DiscoveryProgram. The Drug Discovery Program, founded in 1996 and now a university center, provides a supportiveintellectual infrastructure to assist cooperatoward preclinical drug discovery and eventual commercial development, mainly through outsmall molecule deliverables by Northwestern faculty in the area of CNS drug discoverblockbuster drug marketed by a major pharmaceutical company to potential diseasecandidates with potential for multiple indications that are currently in promising clinical trials.

The academic basic science researchsignal transduction pathways in eukaryotic organisms, examination of their role in physiology and diseasestates, and leveraging of the emergent knowledge of molecular and biological mechpoints of potential therapeutic interventions. He has published in the areas of drug discovery, signaltransduction, structural biology, pharmacology and medicinal chemistry, and previously developeddiagnostic and research tools as

Before moving to Northwestern University, Dr. Watterson held faculty positions at The RockefellerUniversity, where he was an Andrew Mellon Fellow, and at Vanderbilt University Mediwas Professor of Pharmacology and Howard Hughes Investigator. His doctoral training in chemicalsciences was at Emory University, followed by postdoctoral training in biochemistry and bioorganicchemistry at Duke University Medical CenAward from the National Institutes of Health.

Design and Refinement of Novel Small Molecule COverproduction: A Potential Disease

D.M. Watterson, Brinda Braderic, S.M.Roy, V. Tokars, W.F.Anderson, L.J. Van Eldik, C. Borlongan

Northwestern UnivTampa, FL

The inflammatory response is a defense or homeostasis mechanism that responds to various stressors,including infection and injury. However, excessive or prolonged responses as well as immune systemdysfunction can result in tissue injury. Pharmacologicaluse, or highly targeted, such as use of nonresponse modifiers (BRMs). The pharmacological basis of therapeutic action dictates which class ofinteextended pharmacodynamic effects after periodic administration. Many of these protein drugs targetproinflammatory cytokines, effector proteins whose productiodisorders. Currently, extensive efforts in drug development are focused on developing small moleculemodulators of cytokine production to facilitate multiinterventionfindings implicate glia proinflammatory cytokine upneurodegenerative diseases such as Alzheimer’s disease

D. Martin Watterson






Northwestern UnivTampa, FL

The inflammatory response is a defense or homeostasis mechanism that responds to various stressors,including infection and injury. However, excessive or prolonged responses as well as immune systemdysfunction can result in tissue injury. Pharmacologicaluse, or highly targeted, such as use of nonresponse modifiers (BRMs). The pharmacological basis of therapeutic action dictates which class ofinterventions is most appropriate clinically. Current FDAextended pharmacodynamic effects after periodic administration. Many of these protein drugs targetproinflammatory cytokines, effector proteins whose productiodisorders. Currently, extensive efforts in drug development are focused on developing small moleculemodulators of cytokine production to facilitate multiintervention to other indications, such as CNS diseases. In this regard, preclinical studies and clinicalfindings implicate glia proinflammatory cytokine upneurodegenerative diseases such as Alzheimer’s disease

D. Martin Watterson

Daniel Martin Watterson holds the John G. Searle Endowed Chair Professorship atNorthwestern University where he is a Professor in the Department of MolecularPharmacology & Biological Chemistry at the Feinberg School of Medicine. Dr. Wattersonhas workedareas of drug discovery, participated actively in bringing new drug candidates to clinicaldevelopment, served on the Board of Directors for technology companies, foundedprofitable cocolleagues and various government agencies with science and technology development.






Northwestern University,

The inflammatory response is a defense or homeostasis mechanism that responds to various stressors,including infection and injury. However, excessive or prolonged responses as well as immune systemdysfunction can result in tissue injury. Pharmacologicaluse, or highly targeted, such as use of nonresponse modifiers (BRMs). The pharmacological basis of therapeutic action dictates which class of

rventions is most appropriate clinically. Current FDAextended pharmacodynamic effects after periodic administration. Many of these protein drugs targetproinflammatory cytokines, effector proteins whose productiodisorders. Currently, extensive efforts in drug development are focused on developing small moleculemodulators of cytokine production to facilitate multi

to other indications, such as CNS diseases. In this regard, preclinical studies and clinicalfindings implicate glia proinflammatory cytokine upneurodegenerative diseases such as Alzheimer’s disease

D. Martin Watterson, PhD, Northwestern University

Daniel Martin Watterson holds the John G. Searle Endowed Chair Professorship atNorthwestern University where he is a Professor in the Department of MolecularPharmacology & Biological Chemistry at the Feinberg School of Medicine. Dr. Wattersonhas worked successfully with major pharmaceutical and biotech companies in diverseareas of drug discovery, participated actively in bringing new drug candidates to clinicaldevelopment, served on the Board of Directors for technology companies, foundedprofitable commercial enterprises with success in deliverables and timelines, and assistedcolleagues and various government agencies with science and technology development.


The academic basic science researchsignal transduction pathways in eukaryotic organisms, examination of their role in physiology and diseasestates, and leveraging of the emergent knowledge of molecular and biological mechpoints of potential therapeutic interventions. He has published in the areas of drug discovery, signaltransduction, structural biology, pharmacology and medicinal chemistry, and previously developeddiagnostic and research tools as well as novel small molecule therapeutic candidates licensed to industry.




, Chicago, IL; Univ

The inflammatory response is a defense or homeostasis mechanism that responds to various stressors,including infection and injury. However, excessive or prolonged responses as well as immune systemdysfunction can result in tissue injury. Pharmacologicaluse, or highly targeted, such as use of nonresponse modifiers (BRMs). The pharmacological basis of therapeutic action dictates which class of



Northwestern University

Daniel Martin Watterson holds the John G. Searle Endowed Chair Professorship atNorthwestern University where he is a Professor in the Department of MolecularPharmacology & Biological Chemistry at the Feinberg School of Medicine. Dr. Watterson

successfully with major pharmaceutical and biotech companies in diverseareas of drug discovery, participated actively in bringing new drug candidates to clinicaldevelopment, served on the Board of Directors for technology companies, founded

mmercial enterprises with success in deliverables and timelines, and assistedcolleagues and various government agencies with science and technology development.

At Northwestern, he has served as a Department Chair, CoDiscovery and Chemical Biology and a University Center, and founding director of the Drug DiscoveryProgram. The Drug Discovery Program, founded in 1996 and now a university center, provides a supportiveintellectual infrastructure to assist cooperative faculty participants in moving their basic science researchtoward preclinical drug discovery and eventual commercial development, mainly through outsmall molecule deliverables by Northwestern faculty in the area of CNS drug discoverblockbuster drug marketed by a major pharmaceutical company to potential diseasecandidates with potential for multiple indications that are currently in promising clinical trials.

The academic basic science research in Dr. Watterson’s laboratory continues to be on the elucidation ofsignal transduction pathways in eukaryotic organisms, examination of their role in physiology and diseasestates, and leveraging of the emergent knowledge of molecular and biological mechpoints of potential therapeutic interventions. He has published in the areas of drug discovery, signaltransduction, structural biology, pharmacology and medicinal chemistry, and previously developed

well as novel small molecule therapeutic candidates licensed to industry.

Before moving to Northwestern University, Dr. Watterson held faculty positions at The RockefellerUniversity, where he was an Andrew Mellon Fellow, and at Vanderbilt University Mediwas Professor of Pharmacology and Howard Hughes Investigator. His doctoral training in chemicalsciences was at Emory University, followed by postdoctoral training in biochemistry and bioorganicchemistry at Duke University Medical Center where he was supported by a National Research ServiceAward from the National Institutes of Health.

Design and Refinement of Novel Small Molecule COverproduction: A Potential Disease-Modifying Therapeutic


Chicago, IL; University of

The inflammatory response is a defense or homeostasis mechanism that responds to various stressors,including infection and injury. However, excessive or prolonged responses as well as immune systemdysfunction can result in tissue injury. Pharmacologicaluse, or highly targeted, such as use of non-steroidal antiresponse modifiers (BRMs). The pharmacological basis of therapeutic action dictates which class of







At Northwestern, he has served as a Department Chair, CoDiscovery and Chemical Biology and a University Center, and founding director of the Drug DiscoveryProgram. The Drug Discovery Program, founded in 1996 and now a university center, provides a supportive

tive faculty participants in moving their basic science researchtoward preclinical drug discovery and eventual commercial development, mainly through outsmall molecule deliverables by Northwestern faculty in the area of CNS drug discoverblockbuster drug marketed by a major pharmaceutical company to potential diseasecandidates with potential for multiple indications that are currently in promising clinical trials.

in Dr. Watterson’s laboratory continues to be on the elucidation ofsignal transduction pathways in eukaryotic organisms, examination of their role in physiology and diseasestates, and leveraging of the emergent knowledge of molecular and biological mechpoints of potential therapeutic interventions. He has published in the areas of drug discovery, signaltransduction, structural biology, pharmacology and medicinal chemistry, and previously developed


Before moving to Northwestern University, Dr. Watterson held faculty positions at The RockefellerUniversity, where he was an Andrew Mellon Fellow, and at Vanderbilt University Mediwas Professor of Pharmacology and Howard Hughes Investigator. His doctoral training in chemicalsciences was at Emory University, followed by postdoctoral training in biochemistry and bioorganic

ter where he was supported by a National Research Service

Design and Refinement of Novel Small Molecule Compounds Targeting Proinflammatory CytokineModifying Therapeutic


ersity of Kentucky, Lexington, KY; Univ

The inflammatory response is a defense or homeostasis mechanism that responds to various stressors,including infection and injury. However, excessive or prolonged responses as well as immune systemdysfunction can result in tissue injury. Pharmacological intervention can be non

steroidal antiresponse modifiers (BRMs). The pharmacological basis of therapeutic action dictates which class of

rventions is most appropriate clinically. Current FDA-approved BRM drugs are macromolecules withextended pharmacodynamic effects after periodic administration. Many of these protein drugs targetproinflammatory cytokines, effector proteins whose productiodisorders. Currently, extensive efforts in drug development are focused on developing small moleculemodulators of cytokine production to facilitate multi-drug treatment of complex diseases and extend the

to other indications, such as CNS diseases. In this regard, preclinical studies and clinicalfindings implicate glia proinflammatory cytokine up-regulation as a contributor to pathology progression inneurodegenerative diseases such as Alzheimer’s disease, and in the neurologic sequelae resulting from





At Northwestern, he has served as a Department Chair, Co-Director of the Graduate Curriculum iDiscovery and Chemical Biology and a University Center, and founding director of the Drug DiscoveryProgram. The Drug Discovery Program, founded in 1996 and now a university center, provides a supportive






mpounds Targeting Proinflammatory CytokineModifying Therapeutic Approach to CNS D


Kentucky, Lexington, KY; Univ

The inflammatory response is a defense or homeostasis mechanism that responds to various stressors,including infection and injury. However, excessive or prolonged responses as well as immune system

intervention can be nonsteroidal anti-inflammatory drugs (NSAIDs) or biological

response modifiers (BRMs). The pharmacological basis of therapeutic action dictates which class ofapproved BRM drugs are macromolecules with

extended pharmacodynamic effects after periodic administration. Many of these protein drugs targetproinflammatory cytokines, effector proteins whose production is updisorders. Currently, extensive efforts in drug development are focused on developing small molecule

drug treatment of complex diseases and extend theto other indications, such as CNS diseases. In this regard, preclinical studies and clinical

regulation as a contributor to pathology progression in, and in the neurologic sequelae resulting from




Director of the Graduate Curriculum iDiscovery and Chemical Biology and a University Center, and founding director of the Drug DiscoveryProgram. The Drug Discovery Program, founded in 1996 and now a university center, provides a supportive






mpounds Targeting Proinflammatory CytokineApproach to CNS D


Kentucky, Lexington, KY; Univ


intervention can be non-selective, such as steroidinflammatory drugs (NSAIDs) or biological


extended pharmacodynamic effects after periodic administration. Many of these protein drugs targetn is up-regulated in acute and chronic

disorders. Currently, extensive efforts in drug development are focused on developing small moleculedrug treatment of complex diseases and extend the

to other indications, such as CNS diseases. In this regard, preclinical studies and clinicalregulation as a contributor to pathology progression in

, and in the neurologic sequelae resulting from




Director of the Graduate Curriculum iDiscovery and Chemical Biology and a University Center, and founding director of the Drug DiscoveryProgram. The Drug Discovery Program, founded in 1996 and now a university center, provides a supportive

tive faculty participants in moving their basic science researchtoward preclinical drug discovery and eventual commercial development, mainly through out-license. Earliersmall molecule deliverables by Northwestern faculty in the area of CNS drug discovery range from a matureblockbuster drug marketed by a major pharmaceutical company to potential disease-modifying novelcandidates with potential for multiple indications that are currently in promising clinical trials.

in Dr. Watterson’s laboratory continues to be on the elucidation ofsignal transduction pathways in eukaryotic organisms, examination of their role in physiology and diseasestates, and leveraging of the emergent knowledge of molecular and biological mechanisms to identify newpoints of potential therapeutic interventions. He has published in the areas of drug discovery, signaltransduction, structural biology, pharmacology and medicinal chemistry, and previously developed


Before moving to Northwestern University, Dr. Watterson held faculty positions at The RockefellerUniversity, where he was an Andrew Mellon Fellow, and at Vanderbilt University Medical Center, where hewas Professor of Pharmacology and Howard Hughes Investigator. His doctoral training in chemicalsciences was at Emory University, followed by postdoctoral training in biochemistry and bioorganic


mpounds Targeting Proinflammatory CytokineApproach to CNS Diseases


Kentucky, Lexington, KY; University of South Florida,


selective, such as steroidinflammatory drugs (NSAIDs) or biological


extended pharmacodynamic effects after periodic administration. Many of these protein drugs targetregulated in acute and chronic







Director of the Graduate Curriculum in DrugDiscovery and Chemical Biology and a University Center, and founding director of the Drug DiscoveryProgram. The Drug Discovery Program, founded in 1996 and now a university center, provides a supportive

tive faculty participants in moving their basic science researchlicense. Earlier

y range from a maturemodifying novel

in Dr. Watterson’s laboratory continues to be on the elucidation ofsignal transduction pathways in eukaryotic organisms, examination of their role in physiology and disease

anisms to identify newpoints of potential therapeutic interventions. He has published in the areas of drug discovery, signaltransduction, structural biology, pharmacology and medicinal chemistry, and previously developed


Before moving to Northwestern University, Dr. Watterson held faculty positions at The Rockefellercal Center, where he

was Professor of Pharmacology and Howard Hughes Investigator. His doctoral training in chemicalsciences was at Emory University, followed by postdoctoral training in biochemistry and bioorganic


mpounds Targeting Proinflammatory Cytokine


South Florida,











n DrugDiscovery and Chemical Biology and a University Center, and founding director of the Drug DiscoveryProgram. The Drug Discovery Program, founded in 1996 and now a university center, provides a supportive

tive faculty participants in moving their basic science researchlicense. Earlier

y range from a maturemodifying novel

in Dr. Watterson’s laboratory continues to be on the elucidation ofsignal transduction pathways in eukaryotic organisms, examination of their role in physiology and disease

anisms to identify newpoints of potential therapeutic interventions. He has published in the areas of drug discovery, signaltransduction, structural biology, pharmacology and medicinal chemistry, and previously developed

Before moving to Northwestern University, Dr. Watterson held faculty positions at The Rockefellercal Center, where he

was Professor of Pharmacology and Howard Hughes Investigator. His doctoral training in chemicalsciences was at Emory University, followed by postdoctoral training in biochemistry and bioorganic


South Florida,









acute CNS injuries such as traumatic brain injury or ischemia. Therefore, targeting the relevant gliasignaling pathways involved in proinflammatory cytokine overproduction may be a viable, disease-modifying, therapeutic approach. The goal would be restoration of homeostasis by attenuating excessivecytokine production back towards basal, without pan-suppression of all glia responses, using appropriatedoses and intervention time windows relevant to pathology progression.

We are using a validated drug discovery engine in which chemistry, pathobiology, and pharmacology areintegrated early in a recursive effort to design and discover novel, orally bioavailable, CNS-penetrant,selective, small molecule drug candidates that attenuate excessive proinflammatory cytokine productionand improve neurologic end points. One mechanism involved in cytokine overproduction by activated gliaand in neuronal dysfunction is stressor-induced stimulation of protein phosphorylation cascades thatconverge on activation of the p38 MAPK family of protein kinases, especially p38alpha MAPK. We aretesting the hypothesis that p38alpha MAPK is a key in vivo contributor to increased CNS proinflammatorycytokine production and neuronal dysfunction in response to certain disease-relevant stressors, and thatinhibition of p38 MAPK signaling in the CNS can lead to improved neurologic outcomes. Structure andchemoinformatics assisted drug design started with an existing scaffold and provided a novel standard ofcomparison compound with in vivo function. The lead compound serves as the foundation for ongoingmedicinal chemistry refinement and risk reduction activity analyses. Clearly, the p38MAPK targeted drugcandidates might engage the kinase in both glia and neurons, and this dual action via a single moleculartarget could add to desired pharmacodynamic effects. We complemented the single molecular targetapproach for p38 MAPK by using a fragment expansion, phenotypic screening approach with the goal ofdeveloping novel small molecule candidates that also attenuate proinflammatory cytokine up-regulation butare NOT p38MAPK inhibitors. These have proved effective in diverse animal models of disease whereproinflammatory cytokine up-regulation has been implicated in pathology progression. Candidates forclinical development with promising preclinical pharmacological profiles are among the multipledeliverables from this campaign.

Our results provide a preclinical proof of concept that inflammatory cytokine overproduction and theassociated neuronal dysfunction can be attenuated by use of novel small molecules developed by targetingdistinct glia signaling pathways. Deliverables from the two classes of small molecules offer a potentialcomplement to existing and emerging therapeutic approaches to CNS disorders that are characterized byproinflammatory cytokine dysregulation as a mechanism of pathology progression.

28

Donald C. Lo

Director. The Duke CDD currently pursues multiple neurological drug discovery and developmentprograms in collaboration with mresearch foundations.

Optimizing New Drug Candidates for Protein Disulfide Isomerase, A Novel Target forNeurodegenerative Diseases

Donald C. Lo

Duke University Medical Center

Current therapies for Alzheimer's disease (AD) provide modest symptomatic relief but none of these fewFDAthe neuropathogenesis that is cdevelop innovative new drug strategies that may intervene at different points in the biological pathways thatunderlie pathogenesis in AD.In a multithe discovery and development of new drug candidates for neurodegenerative diseases including AD andHuntington's disease (HD). Because AD and HD are fundamentally protein misfolding diselikely share core degenerative mechanisms and pathways, we have originated some screens in highthroughput HD assays that we have subsequently validated in brain slice as well as in vivo models for bothHD and AD.We describe here our recentpathway in neurodegeneration induced by misfolded proteins such as Aβ, protein disulfide isomerase (PDI). Current studies are focused on developing secondwith improved drugbrain slice

Donald C. Lo



Donald C. Lo


Current therapies for Alzheimer's disease (AD) provide modest symptomatic relief but none of these fewFDA-approved drugs can delay or halt the progression of AD, or, critically, provide direct protection againstthe neuropathogenesis that is cdevelop innovative new drug strategies that may intervene at different points in the biological pathways thatunderlie pathogenesis in AD.In a multi-year collaboration with Dr.the discovery and development of new drug candidates for neurodegenerative diseases including AD andHuntington's disease (HD). Because AD and HD are fundamentally protein misfolding diselikely share core degenerative mechanisms and pathways, we have originated some screens in highthroughput HD assays that we have subsequently validated in brain slice as well as in vivo models for bothHD and AD.We describe here our recentpathway in neurodegeneration induced by misfolded proteins such as Aβ, protein disulfide isomerase (PDI). Current studies are focused on developing secondwith improved drugbrain slice-based assays for AD.

Donald C. Lo, PhD,

Donald Lo is an AssociateUniversity Medical Center, and has been engaged in drug discovery and development forneurodegenerative disorders and stroke for over 10 years. In 1997, he cowas Chief Scientific Officer ofdeveloped and implemented brain tissue basedand Alzheimer's disease, the latter two indications in joint ventures with ElanPharmaceuticals. In 2002, this technincorporated into the new Center for Drug Discovery (CDD) for which Lo serves as




Current therapies for Alzheimer's disease (AD) provide modest symptomatic relief but none of these fewapproved drugs can delay or halt the progression of AD, or, critically, provide direct protection against

the neuropathogenesis that is cdevelop innovative new drug strategies that may intervene at different points in the biological pathways thatunderlie pathogenesis in AD.

year collaboration with Dr.the discovery and development of new drug candidates for neurodegenerative diseases including AD andHuntington's disease (HD). Because AD and HD are fundamentally protein misfolding diselikely share core degenerative mechanisms and pathways, we have originated some screens in highthroughput HD assays that we have subsequently validated in brain slice as well as in vivo models for both

We describe here our recentpathway in neurodegeneration induced by misfolded proteins such as Aβ, protein disulfide isomerase (PDI). Current studies are focused on developing secondwith improved drug-like properties, blood brain barrier penetrability, and their testing and prioritization in

based assays for AD.

, PhD, Duke University Medical Center

Donald Lo is an AssociateUniversity Medical Center, and has been engaged in drug discovery and development forneurodegenerative disorders and stroke for over 10 years. In 1997, he cowas Chief Scientific Officer ofdeveloped and implemented brain tissue basedand Alzheimer's disease, the latter two indications in joint ventures with ElanPharmaceuticals. In 2002, this technincorporated into the new Center for Drug Discovery (CDD) for which Lo serves as

Director. The Duke CDD currently pursues multiple neurological drug discovery and developmentprograms in collaboration with major pharmaceutical firms, biotech companies, and non


Duke University Medical Center, Durham, NC


the neuropathogenesis that is core to the disease process. In this context, there remains an urgent need todevelop innovative new drug strategies that may intervene at different points in the biological pathways thatunderlie pathogenesis in AD.

year collaboration with Dr.the discovery and development of new drug candidates for neurodegenerative diseases including AD andHuntington's disease (HD). Because AD and HD are fundamentally protein misfolding diselikely share core degenerative mechanisms and pathways, we have originated some screens in highthroughput HD assays that we have subsequently validated in brain slice as well as in vivo models for both

We describe here our recent collaborative work indicating the druggability of a newly identified cell deathpathway in neurodegeneration induced by misfolded proteins such as Aβ, protein disulfide isomerase (PDI). Current studies are focused on developing second

like properties, blood brain barrier penetrability, and their testing and prioritization inbased assays for AD.


Donald Lo is an Associate Professor in the Department of Neurobiology at DukeUniversity Medical Center, and has been engaged in drug discovery and development forneurodegenerative disorders and stroke for over 10 years. In 1997, he cowas Chief Scientific Officer ofdeveloped and implemented brain tissue basedand Alzheimer's disease, the latter two indications in joint ventures with ElanPharmaceuticals. In 2002, this technincorporated into the new Center for Drug Discovery (CDD) for which Lo serves as

Director. The Duke CDD currently pursues multiple neurological drug discovery and developmentajor pharmaceutical firms, biotech companies, and non

Optimizing New Drug Candidates for Protein Disulfide Isomerase, A Novel Target for

Durham, NC


ore to the disease process. In this context, there remains an urgent need todevelop innovative new drug strategies that may intervene at different points in the biological pathways that

year collaboration with Dr. Brent Stockwell's lab at Columbia University, we have been pursuingthe discovery and development of new drug candidates for neurodegenerative diseases including AD andHuntington's disease (HD). Because AD and HD are fundamentally protein misfolding diselikely share core degenerative mechanisms and pathways, we have originated some screens in highthroughput HD assays that we have subsequently validated in brain slice as well as in vivo models for both

collaborative work indicating the druggability of a newly identified cell deathpathway in neurodegeneration induced by misfolded proteins such as Aβ, protein disulfide isomerase (PDI). Current studies are focused on developing second

like properties, blood brain barrier penetrability, and their testing and prioritization in


Professor in the Department of Neurobiology at DukeUniversity Medical Center, and has been engaged in drug discovery and development forneurodegenerative disorders and stroke for over 10 years. In 1997, he cowas Chief Scientific Officer of the biotechnology company Cogent Neuroscience, whichdeveloped and implemented brain tissue basedand Alzheimer's disease, the latter two indications in joint ventures with ElanPharmaceuticals. In 2002, this technology was brought back into Duke University andincorporated into the new Center for Drug Discovery (CDD) for which Lo serves as





Brent Stockwell's lab at Columbia University, we have been pursuingthe discovery and development of new drug candidates for neurodegenerative diseases including AD andHuntington's disease (HD). Because AD and HD are fundamentally protein misfolding diselikely share core degenerative mechanisms and pathways, we have originated some screens in highthroughput HD assays that we have subsequently validated in brain slice as well as in vivo models for both

collaborative work indicating the druggability of a newly identified cell deathpathway in neurodegeneration induced by misfolded proteins such as Aβ, protein disulfide isomerase (PDI). Current studies are focused on developing second-generation lead can

like properties, blood brain barrier penetrability, and their testing and prioritization in


Professor in the Department of Neurobiology at DukeUniversity Medical Center, and has been engaged in drug discovery and development forneurodegenerative disorders and stroke for over 10 years. In 1997, he co

the biotechnology company Cogent Neuroscience, whichdeveloped and implemented brain tissue based-assays for stroke, Huntington's disease,and Alzheimer's disease, the latter two indications in joint ventures with Elan

ology was brought back into Duke University andincorporated into the new Center for Drug Discovery (CDD) for which Lo serves as






collaborative work indicating the druggability of a newly identified cell deathpathway in neurodegeneration induced by misfolded proteins such as Aβ, protein disulfide isomerase (PDI).

generation lead canlike properties, blood brain barrier penetrability, and their testing and prioritization in

Professor in the Department of Neurobiology at DukeUniversity Medical Center, and has been engaged in drug discovery and development forneurodegenerative disorders and stroke for over 10 years. In 1997, he co

the biotechnology company Cogent Neuroscience, whichassays for stroke, Huntington's disease,

and Alzheimer's disease, the latter two indications in joint ventures with Elanology was brought back into Duke University and

incorporated into the new Center for Drug Discovery (CDD) for which Lo serves asDirector. The Duke CDD currently pursues multiple neurological drug discovery and development

ajor pharmaceutical firms, biotech companies, and non






generation lead candidate compounds targeting PDIlike properties, blood brain barrier penetrability, and their testing and prioritization in

Professor in the Department of Neurobiology at DukeUniversity Medical Center, and has been engaged in drug discovery and development forneurodegenerative disorders and stroke for over 10 years. In 1997, he co-founded and

the biotechnology company Cogent Neuroscience, whichassays for stroke, Huntington's disease,

and Alzheimer's disease, the latter two indications in joint ventures with Elanology was brought back into Duke University and

incorporated into the new Center for Drug Discovery (CDD) for which Lo serves asDirector. The Duke CDD currently pursues multiple neurological drug discovery and development

ajor pharmaceutical firms, biotech companies, and non-profit disease




Brent Stockwell's lab at Columbia University, we have been pursuingthe discovery and development of new drug candidates for neurodegenerative diseases including AD andHuntington's disease (HD). Because AD and HD are fundamentally protein misfolding diseases that verylikely share core degenerative mechanisms and pathways, we have originated some screens in highthroughput HD assays that we have subsequently validated in brain slice as well as in vivo models for both


didate compounds targeting PDIlike properties, blood brain barrier penetrability, and their testing and prioritization in

Professor in the Department of Neurobiology at DukeUniversity Medical Center, and has been engaged in drug discovery and development for

founded andthe biotechnology company Cogent Neuroscience, which

assays for stroke, Huntington's disease,and Alzheimer's disease, the latter two indications in joint ventures with Elan


Director. The Duke CDD currently pursues multiple neurological drug discovery and developmentprofit disease



Brent Stockwell's lab at Columbia University, we have been pursuingthe discovery and development of new drug candidates for neurodegenerative diseases including AD and

ases that verylikely share core degenerative mechanisms and pathways, we have originated some screens in high-throughput HD assays that we have subsequently validated in brain slice as well as in vivo models for both



Professor in the Department of Neurobiology at DukeUniversity Medical Center, and has been engaged in drug discovery and development for

founded andthe biotechnology company Cogent Neuroscience, which

assays for stroke, Huntington's disease,and Alzheimer's disease, the latter two indications in joint ventures with Elan


Director. The Duke CDD currently pursues multiple neurological drug discovery and developmentprofit disease



Brent Stockwell's lab at Columbia University, we have been pursuingthe discovery and development of new drug candidates for neurodegenerative diseases including AD and

ases that very

throughput HD assays that we have subsequently validated in brain slice as well as in vivo models for both




RobertUniv

pathapproaches to converting apoE4 to apoE3 both structurally and functionally and preventing the generationof apoE4 neurotoxic fragments. Dr. Mahley is also aof California, San Francisco. He is a member of the National Academy of Sciences, the Institute ofMedicine, and the American Academy of Arts & Sciences. He recently received the Builders of ScienceAwits growth to become one of the world’s foremost independent research institutes.

ProofDetrimental Effects of Apolipoprotein E4 in Vitro by Inhibiting Domain Interaction

Robert

Gladstone In

Apolipoprotein (apo) E4, the major genepathological conformationdomain interaction were identified by fluorescence resonance energy transfer (FRET) assay. ScreeningChemBridge library identified CB9032258 (a phthalazinone derivative, N2-(IC50: 4.2 μM). Chemical modification of CB903(e.g., Nmethylwith enhanced FRET potencies (IC50: 23 and 116 nM, respectively). ApoE4 domain interaction is known tomediate the apoE4reducing mitochondrial motilityderivatives restored these cellular functions to levels equivalent to those of apoE3. Results from thefunctional assays correlated well with the abilities of small molecules to blocConclusion: We have established that specific phthalazinone derivatives are capable of disrupting domaininteraction of newly synthesized apoE4 in the secretory pathway and reversing apoE4effects on neuronastructural correctors can negate the detrimental effects of apoE4 and suggests a potential therapeuticapproach.


Robert W.University of California, San Francisco

pathogenesis of Alzheimer’s disease and neurodegeneration. More recently, he has focused on therapeuticapproaches to converting apoE4 to apoE3 both structurally and functionally and preventing the generationof apoE4 neurotoxic fragments. Dr. Mahley is also aof California, San Francisco. He is a member of the National Academy of Sciences, the Institute ofMedicine, and the American Academy of Arts & Sciences. He recently received the Builders of ScienceAward from Research!America for his leadership as Gladstone’s founding director and president, guidingits growth to become one of the world’s foremost independent research institutes.

Proof-of-Concept That Small Molecule Structure Correctors Are Capable oDetrimental Effects of Apolipoprotein E4 in Vitro by Inhibiting Domain Interaction

Robert W. Mahley

Gladstone Institute of Neurological Disease

Apolipoprotein (apo) E4, the major genepathological conformationdomain interaction were identified by fluorescence resonance energy transfer (FRET) assay. ScreeningChemBridge library identified CB9032258 (a phthalazinone derivative, N

-(3-methyl-4(IC50: 4.2 μM). Chemical modification of CB903(e.g., N-(4′-cyanomethyl-4-oxo-with enhanced FRET potencies (IC50: 23 and 116 nM, respectively). ApoE4 domain interaction is known tomediate the apoE4reducing mitochondrial motilityderivatives restored these cellular functions to levels equivalent to those of apoE3. Results from thefunctional assays correlated well with the abilities of small molecules to blocConclusion: We have established that specific phthalazinone derivatives are capable of disrupting domaininteraction of newly synthesized apoE4 in the secretory pathway and reversing apoE4effects on neuronastructural correctors can negate the detrimental effects of apoE4 and suggests a potential therapeuticapproach.


W. Mahley, MD,ersity of California, San Francisco

Dr. Robert W. Mahley is president emeritus/founder/senior investigator of The J. DavidGladstone Institutes. He is an internationally known expert on heart disease, cholesterolmetabolism and, more recently,particularly apolipoprotein (apo) E. His seminal research has defined apoE’s critical role incholesterol homeostasis and atherosclerosis. Dr. Mahley has also made fundamentalcontributions to understinjury and regeneration and in the remodeling of neurites on neuronal cells. These findingslaid the groundwork for the explosion of research linking apoE4, a variant of apoE, to the

ogenesis of Alzheimer’s disease and neurodegeneration. More recently, he has focused on therapeuticapproaches to converting apoE4 to apoE3 both structurally and functionally and preventing the generationof apoE4 neurotoxic fragments. Dr. Mahley is also aof California, San Francisco. He is a member of the National Academy of Sciences, the Institute ofMedicine, and the American Academy of Arts & Sciences. He recently received the Builders of Science

ard from Research!America for his leadership as Gladstone’s founding director and president, guidingits growth to become one of the world’s foremost independent research institutes.

oncept That Small Molecule Structure Correctors Are Capable oDetrimental Effects of Apolipoprotein E4 in Vitro by Inhibiting Domain Interaction

Mahley

stitute of Neurological Disease

Apolipoprotein (apo) E4, the major genepathological conformationdomain interaction were identified by fluorescence resonance energy transfer (FRET) assay. ScreeningChemBridge library identified CB9032258 (a phthalazinone derivative, N

4-oxo-3,4-dihydro(IC50: 4.2 μM). Chemical modification of CB903

cyano-biphenyl-3,4-dihydro

with enhanced FRET potencies (IC50: 23 and 116 nM, respectively). ApoE4 domain interaction is known tomediate the apoE4-specific effects of decreasing mitochondrial cytochrome c oxidase subunit 1 (~40%),reducing mitochondrial motilityderivatives restored these cellular functions to levels equivalent to those of apoE3. Results from thefunctional assays correlated well with the abilities of small molecules to blocConclusion: We have established that specific phthalazinone derivatives are capable of disrupting domaininteraction of newly synthesized apoE4 in the secretory pathway and reversing apoE4effects on neuronal cells. These results serve as a proofstructural correctors can negate the detrimental effects of apoE4 and suggests a potential therapeutic


Mahley, MD, PhDersity of California, San Francisco

Dr. Robert W. Mahley is president emeritus/founder/senior investigator of The J. DavidGladstone Institutes. He is an internationally known expert on heart disease, cholesterolmetabolism and, more recently,particularly apolipoprotein (apo) E. His seminal research has defined apoE’s critical role incholesterol homeostasis and atherosclerosis. Dr. Mahley has also made fundamentalcontributions to understinjury and regeneration and in the remodeling of neurites on neuronal cells. These findingslaid the groundwork for the explosion of research linking apoE4, a variant of apoE, to the




stitute of Neurological Disease

Apolipoprotein (apo) E4, the major genepathological conformation—intramolecular domain interaction. ApoE structure correctors that abolishdomain interaction were identified by fluorescence resonance energy transfer (FRET) assay. ScreeningChemBridge library identified CB9032258 (a phthalazinone derivative, N

dihydro-phthalazin(IC50: 4.2 μM). Chemical modification of CB903

biphenyl-3-yl)-2-(3dihydro-phthalazin-

with enhanced FRET potencies (IC50: 23 and 116 nM, respectively). ApoE4 domain interaction is known tospecific effects of decreasing mitochondrial cytochrome c oxidase subunit 1 (~40%),

reducing mitochondrial motility (~35%), and significantly inhibiting neurite outgrowth. CB9032258 and itsderivatives restored these cellular functions to levels equivalent to those of apoE3. Results from thefunctional assays correlated well with the abilities of small molecules to blocConclusion: We have established that specific phthalazinone derivatives are capable of disrupting domaininteraction of newly synthesized apoE4 in the secretory pathway and reversing apoE4

l cells. These results serve as a proofstructural correctors can negate the detrimental effects of apoE4 and suggests a potential therapeutic

PhD, Gladstone Institute of Neurersity of California, San Francisco

Dr. Robert W. Mahley is president emeritus/founder/senior investigator of The J. DavidGladstone Institutes. He is an internationally known expert on heart disease, cholesterolmetabolism and, more recently,particularly apolipoprotein (apo) E. His seminal research has defined apoE’s critical role incholesterol homeostasis and atherosclerosis. Dr. Mahley has also made fundamentalcontributions to understanding the role of apoE in the nervous system, specifically in nerveinjury and regeneration and in the remodeling of neurites on neuronal cells. These findingslaid the groundwork for the explosion of research linking apoE4, a variant of apoE, to the




stitute of Neurological Disease and University of California, San Francisco

Apolipoprotein (apo) E4, the major gene and risk factor for Alzheimer’s disease (AD), assumes aintramolecular domain interaction. ApoE structure correctors that abolish

domain interaction were identified by fluorescence resonance energy transfer (FRET) assay. ScreeningChemBridge library identified CB9032258 (a phthalazinone derivative, N

phthalazin-1-yl)-acetamide) that reduces the FRET signal dose(IC50: 4.2 μM). Chemical modification of CB903

(3-methyl-4-oxo-1-yl)-acetylami


(~35%), and significantly inhibiting neurite outgrowth. CB9032258 and itsderivatives restored these cellular functions to levels equivalent to those of apoE3. Results from thefunctional assays correlated well with the abilities of small molecules to blocConclusion: We have established that specific phthalazinone derivatives are capable of disrupting domaininteraction of newly synthesized apoE4 in the secretory pathway and reversing apoE4

l cells. These results serve as a proofstructural correctors can negate the detrimental effects of apoE4 and suggests a potential therapeutic

Gladstone Institute of Neurersity of California, San Francisco

Dr. Robert W. Mahley is president emeritus/founder/senior investigator of The J. DavidGladstone Institutes. He is an internationally known expert on heart disease, cholesterolmetabolism and, more recently, Alzheimer’s disease. He studies plasma lipoproteins andparticularly apolipoprotein (apo) E. His seminal research has defined apoE’s critical role incholesterol homeostasis and atherosclerosis. Dr. Mahley has also made fundamental

anding the role of apoE in the nervous system, specifically in nerveinjury and regeneration and in the remodeling of neurites on neuronal cells. These findingslaid the groundwork for the explosion of research linking apoE4, a variant of apoE, to the

ogenesis of Alzheimer’s disease and neurodegeneration. More recently, he has focused on therapeuticapproaches to converting apoE4 to apoE3 both structurally and functionally and preventing the generationof apoE4 neurotoxic fragments. Dr. Mahley is also a professor of medicine and pathology at the Universityof California, San Francisco. He is a member of the National Academy of Sciences, the Institute ofMedicine, and the American Academy of Arts & Sciences. He recently received the Builders of Science



and University of California, San Francisco

and risk factor for Alzheimer’s disease (AD), assumes aintramolecular domain interaction. ApoE structure correctors that abolish


acetamide) that reduces the FRET signal dose(IC50: 4.2 μM). Chemical modification of CB9032258 yielded well

oxo-3,4-dihydroacetylamino]-benzyl}



l cells. These results serve as a proof-ofstructural correctors can negate the detrimental effects of apoE4 and suggests a potential therapeutic

Gladstone Institute of Neur

Dr. Robert W. Mahley is president emeritus/founder/senior investigator of The J. DavidGladstone Institutes. He is an internationally known expert on heart disease, cholesterol

Alzheimer’s disease. He studies plasma lipoproteins andparticularly apolipoprotein (apo) E. His seminal research has defined apoE’s critical role incholesterol homeostasis and atherosclerosis. Dr. Mahley has also made fundamental


ogenesis of Alzheimer’s disease and neurodegeneration. More recently, he has focused on therapeuticapproaches to converting apoE4 to apoE3 both structurally and functionally and preventing the generation

professor of medicine and pathology at the Universityof California, San Francisco. He is a member of the National Academy of Sciences, the Institute ofMedicine, and the American Academy of Arts & Sciences. He recently received the Builders of Science






acetamide) that reduces the FRET signal dose2258 yielded well-defined structure

dihydro-phthalazinbenzyl}-piperazine



of-concept that pharmacological intervention bystructural correctors can negate the detrimental effects of apoE4 and suggests a potential therapeutic

Gladstone Institute of Neurological Dis







oncept That Small Molecule Structure Correctors Are Capable of Abolishing theDetrimental Effects of Apolipoprotein E4 in Vitro by Inhibiting Domain Interaction



domain interaction were identified by fluorescence resonance energy transfer (FRET) assay. ScreeningChemBridge library identified CB9032258 (a phthalazinone derivative, N-(2-hydroxy

acetamide) that reduces the FRET signal dosedefined structure

phthalazin-1-yl)-acetamidepiperazine-1-carboxylic acid


(~35%), and significantly inhibiting neurite outgrowth. CB9032258 and itsderivatives restored these cellular functions to levels equivalent to those of apoE3. Results from thefunctional assays correlated well with the abilities of small molecules to block apoE4 domain interaction.Conclusion: We have established that specific phthalazinone derivatives are capable of disrupting domaininteraction of newly synthesized apoE4 in the secretory pathway and reversing apoE4

concept that pharmacological intervention bystructural correctors can negate the detrimental effects of apoE4 and suggests a potential therapeutic

ological Disease and






ard from Research!America for his leadership as Gladstone’s founding director and president, guiding

f Abolishing theDetrimental Effects of Apolipoprotein E4 in Vitro by Inhibiting Domain Interaction

and University of California, San Francisco, CA


domain interaction were identified by fluorescence resonance energy transfer (FRET) assay. Screeninghydroxy-3,5-dimethyl

acetamide) that reduces the FRET signal dose-dependentlydefined structure-activity relationships

acetamide and 4carboxylic acid tert


(~35%), and significantly inhibiting neurite outgrowth. CB9032258 and itsderivatives restored these cellular functions to levels equivalent to those of apoE3. Results from the

k apoE4 domain interaction.Conclusion: We have established that specific phthalazinone derivatives are capable of disrupting domaininteraction of newly synthesized apoE4 in the secretory pathway and reversing apoE4-specific detrimental


29

and







f Abolishing the


domain interaction were identified by fluorescence resonance energy transfer (FRET) assay. Screening adimethyl-phenyl)-

dependentlyactivity relationships

and 4-{4-[2-(3-tert-butyl ester)


(~35%), and significantly inhibiting neurite outgrowth. CB9032258 and itsderivatives restored these cellular functions to levels equivalent to those of apoE3. Results from the

k apoE4 domain interaction.Conclusion: We have established that specific phthalazinone derivatives are capable of disrupting domain

specific detrimentalconcept that pharmacological intervention by

structural correctors can negate the detrimental effects of apoE4 and suggests a potential therapeutic








a

dependentlyactivity relationships

butyl ester)with enhanced FRET potencies (IC50: 23 and 116 nM, respectively). ApoE4 domain interaction is known to

specific effects of decreasing mitochondrial cytochrome c oxidase subunit 1 (~40%),(~35%), and significantly inhibiting neurite outgrowth. CB9032258 and its

derivatives restored these cellular functions to levels equivalent to those of apoE3. Results from thek apoE4 domain interaction.

Conclusion: We have established that specific phthalazinone derivatives are capable of disrupting domainspecific detrimental


30

Allen Reitz

early drug discovery with a core competency in medicinal chemistry.

Tau Lowering Agents for

Allen Reitz

ALS Biopharma, LLC

The structural protein tau is implicated in the pathology of Alzheimer’s disease. The heat shock responseis upregulated upon physiological and oxidative stress, and one of the key heat shock proteins implicatedin this process is Hsp70. Hsp70 helps to prelevance to Alzheimer’s disease, tau is a client protein for Hsp70 and updecrease in tau levels. Agents that penetrate into the brain and lower tau, by any mechanismpotential to provide disease

We have performed a series of screening studies using a drugunderstand the relation of structure

•••

We have identified compounds that are individually active in all of these assays. Of particular note, wehave identified small molecule hitchemistry to understand the structural determinants of this biological effect, and are seeking to obtainbrainbehavior in these models. If this approach is further validated in early drug discovery research, then one ormore of the compounds we discover may prove to be useful as therapeutics to treat Alzheimer’s disease.

Allen Reitz



Allen Reitz

ALS Biopharma, LLC



• inhibition of Hsp90,• up-regulation of Hsp70, and• down-regulation of tau.

We have identified compounds that are individually active in all of these assays. Of particular note, wehave identified small molecule hitchemistry to understand the structural determinants of this biological effect, and are seeking to obtainbrain-penetrant, metabolicallybehavior in these models. If this approach is further validated in early drug discovery research, then one ormore of the compounds we discover may prove to be useful as therapeutics to treat Alzheimer’s disease.

Allen Reitz, PhD, ALS Biopharma, LLC

Allen Reitz,(www.alsbiopharma.com), based at the Pennsylvania Biotechnology Center in Doylestown,PA. He received aat Johnson & Johnson for nearlyprimarily in the area of CNS research including neurology and Alzheimer’s disease. He isinventor of 46 issued U.S. patents resulting in seven compounds that have enteclinical trials, has greaEditor of the journal Current Topics in Medicinal Chemistry. His research interests include



ALS Biopharma, LLC, Doylestown, PA



inhibition of Hsp90,regulation of Hsp70, and

regulation of tau.

We have identified compounds that are individually active in all of these assays. Of particular note, wehave identified small molecule hitchemistry to understand the structural determinants of this biological effect, and are seeking to obtain

penetrant, metabolicallybehavior in these models. If this approach is further validated in early drug discovery research, then one ormore of the compounds we discover may prove to be useful as therapeutics to treat Alzheimer’s disease.

ALS Biopharma, LLC

Allen Reitz, PhD(www.alsbiopharma.com), based at the Pennsylvania Biotechnology Center in Doylestown,PA. He received a PhDat Johnson & Johnson for nearlyprimarily in the area of CNS research including neurology and Alzheimer’s disease. He isinventor of 46 issued U.S. patents resulting in seven compounds that have enteclinical trials, has greaEditor of the journal Current Topics in Medicinal Chemistry. His research interests include


Tau Lowering Agents for the Treatment of Alzheimer’s Disease

, Doylestown, PA

The structural protein tau is implicated in the pathology of Alzheimer’s disease. The heat shock responseis upregulated upon physiological and oxidative stress, and one of the key heat shock proteins implicatedin this process is Hsp70. Hsp70 helps to prelevance to Alzheimer’s disease, tau is a client protein for Hsp70 and updecrease in tau levels. Agents that penetrate into the brain and lower tau, by any mechanismpotential to provide disease-modifying therapeutic relief for patients suffering from Alzheimer’s disease.

We have performed a series of screening studies using a drugunderstand the relation of structure to function for the following effects:

inhibition of Hsp90,regulation of Hsp70, and

regulation of tau.

We have identified compounds that are individually active in all of these assays. Of particular note, wehave identified small molecule hits that lower tau levels in cell culture. We have conducted medicinalchemistry to understand the structural determinants of this biological effect, and are seeking to obtain

penetrant, metabolically-stable analogs that lower tau as probes to determibehavior in these models. If this approach is further validated in early drug discovery research, then one ormore of the compounds we discover may prove to be useful as therapeutics to treat Alzheimer’s disease.

ALS Biopharma, LLC

PhD, is co(www.alsbiopharma.com), based at the Pennsylvania Biotechnology Center in Doylestown,

PhD in Chemistry from the University of California, San Diego and wasat Johnson & Johnson for nearlyprimarily in the area of CNS research including neurology and Alzheimer’s disease. He isinventor of 46 issued U.S. patents resulting in seven compounds that have enteclinical trials, has greater than 130 publications in peerEditor of the journal Current Topics in Medicinal Chemistry. His research interests include


the Treatment of Alzheimer’s Disease

, Doylestown, PA

The structural protein tau is implicated in the pathology of Alzheimer’s disease. The heat shock responseis upregulated upon physiological and oxidative stress, and one of the key heat shock proteins implicatedin this process is Hsp70. Hsp70 helps to promote the refolding of misfolded proteins. Of particularrelevance to Alzheimer’s disease, tau is a client protein for Hsp70 and updecrease in tau levels. Agents that penetrate into the brain and lower tau, by any mechanism

modifying therapeutic relief for patients suffering from Alzheimer’s disease.

We have performed a series of screening studies using a drugto function for the following effects:

We have identified compounds that are individually active in all of these assays. Of particular note, wes that lower tau levels in cell culture. We have conducted medicinal

chemistry to understand the structural determinants of this biological effect, and are seeking to obtainstable analogs that lower tau as probes to determi

behavior in these models. If this approach is further validated in early drug discovery research, then one ormore of the compounds we discover may prove to be useful as therapeutics to treat Alzheimer’s disease.

ALS Biopharma, LLC

, is co-founder and CEO of ALS Biopharma, LLC(www.alsbiopharma.com), based at the Pennsylvania Biotechnology Center in Doylestown,

in Chemistry from the University of California, San Diego and wasat Johnson & Johnson for nearly 26 years at the Spring House, Pennsylvania facility,primarily in the area of CNS research including neurology and Alzheimer’s disease. He isinventor of 46 issued U.S. patents resulting in seven compounds that have ente

130 publications in peerEditor of the journal Current Topics in Medicinal Chemistry. His research interests include



The structural protein tau is implicated in the pathology of Alzheimer’s disease. The heat shock responseis upregulated upon physiological and oxidative stress, and one of the key heat shock proteins implicated

romote the refolding of misfolded proteins. Of particularrelevance to Alzheimer’s disease, tau is a client protein for Hsp70 and updecrease in tau levels. Agents that penetrate into the brain and lower tau, by any mechanism


We have performed a series of screening studies using a drugto function for the following effects:




founder and CEO of ALS Biopharma, LLC(www.alsbiopharma.com), based at the Pennsylvania Biotechnology Center in Doylestown,

in Chemistry from the University of California, San Diego and was26 years at the Spring House, Pennsylvania facility,

primarily in the area of CNS research including neurology and Alzheimer’s disease. He isinventor of 46 issued U.S. patents resulting in seven compounds that have ente

130 publications in peer-Editor of the journal Current Topics in Medicinal Chemistry. His research interests include




romote the refolding of misfolded proteins. Of particularrelevance to Alzheimer’s disease, tau is a client protein for Hsp70 and updecrease in tau levels. Agents that penetrate into the brain and lower tau, by any mechanism


We have performed a series of screening studies using a drug-like, chemicallyto function for the following effects:







130 publications in peer-reviewed scientific journals, and isEditor of the journal Current Topics in Medicinal Chemistry. His research interests include


romote the refolding of misfolded proteins. Of particularrelevance to Alzheimer’s disease, tau is a client protein for Hsp70 and up-regulation of Hsp70 causes adecrease in tau levels. Agents that penetrate into the brain and lower tau, by any mechanism


like, chemically


chemistry to understand the structural determinants of this biological effect, and are seeking to obtainstable analogs that lower tau as probes to determine how such activity alters





reviewed scientific journals, and isEditor of the journal Current Topics in Medicinal Chemistry. His research interests include


romote the refolding of misfolded proteins. Of particularregulation of Hsp70 causes a

decrease in tau levels. Agents that penetrate into the brain and lower tau, by any mechanismmodifying therapeutic relief for patients suffering from Alzheimer’s disease.

like, chemically-diverse library, to


chemistry to understand the structural determinants of this biological effect, and are seeking to obtainne how such activity alters




primarily in the area of CNS research including neurology and Alzheimer’s disease. He isinventor of 46 issued U.S. patents resulting in seven compounds that have entered human




decrease in tau levels. Agents that penetrate into the brain and lower tau, by any mechanism, have themodifying therapeutic relief for patients suffering from Alzheimer’s disease.

diverse library, to






primarily in the area of CNS research including neurology and Alzheimer’s disease. He isred human




, have the

diverse library, to



behavior in these models. If this approach is further validated in early drug discovery research, then one or


Brandon

using a combination of NMR spectroscopy, MALDI/TOF and molecular modeling techniques.

Since joining Amicus in 2002, he has applied a wide variety of analytical, biotechniques to 1) better understand the cellular pathologies of various lysosomal storage disorders and theirrelationship to other more common neurodegenerative disorders and 2) to study the effects ofpharmacological chaperonediscovery efforts and mechanismthat entered clinical trials as potential treatments for Fabry (Phase 3(Phase 2) diseases. Additionally, his lab has been exploring how impaired glycosphingolipid/gangliosidemetabolism may contribute to neurodegeneration and developing pharmacological chaperones that canmodulate lipid metaboliAlzheimer’s. We have identified several animal models with impaired glycosphingolipid catabolism thatdevelop PDglycosphingolipid metabolism disorders and various neurodegenerative diseases (e.g., Gaucher andParkinson’s diseases) and to examine the effectiveness of pharmacological chaperone treatment. In 2006,his team received a “Thethe use of chaperones for the treatment of Parkinson’s disease and now several molecules are inadvanced preclinical development for PD. In 2010, he received a grant froDiscovery Foundation which is focused on demonstrating in vivo proofganglioside catabolism as a potential therapy for Alzheimer’s disease. Additionally, his team is currentlydeveloping presenilinAlzheimer’s disease.

Modulation of Ganglioside Catabolism Using Pharmacological Chaperones: A Novel TherapeuticApproach for Alzheimer’s Disease

Brandon A. Wustman

1Amicus Therapeutics

Many neurodegenerative disorders are characterized by the accumulation and aggregation of amyloidpeptide (Aβ)system as a central cause of these disorders, supported by the genetic link between Parkinson’s diseaseand the lysosomal storage disorder (LSD) Gaucher disease. As a result, we have investigatelinks between other LSDs and neurodegenerative disorders (e.g., Alzheimer’s disease). Sinceintraneuronal Aβ accumulation has been observed in a mouse model of Sandhoff disease and gangliosides have been shown to promote Aβ oligomerization in viand hippocampus) from individuals with GM1 and GM2 gangliosidoses (GM1 gangliosidosis, Taydisease, and Sandoff disease; n = 8), Alzheimer’s disease (AD, n=2) and ageobservimmunoreactivity, and αAmyloid plaques and neurofibrillary tangles were observed inproposed to act as a nucleation seed for Aβ oligomerization, and is thus thought to represent a preaggregate in AD.


Brandon Wustman


Since joining Amicus in 2002, he has applied a wide variety of analytical, biotechniques to 1) better understand the cellular pathologies of various lysosomal storage disorders and theirrelationship to other more common neurodegenerative disorders and 2) to study the effects ofpharmacological chaperonediscovery efforts and mechanismthat entered clinical trials as potential treatments for Fabry (Phase 3(Phase 2) diseases. Additionally, his lab has been exploring how impaired glycosphingolipid/gangliosidemetabolism may contribute to neurodegeneration and developing pharmacological chaperones that canmodulate lipid metaboliAlzheimer’s. We have identified several animal models with impaired glycosphingolipid catabolism thatdevelop PD- and ADglycosphingolipid metabolism disorders and various neurodegenerative diseases (e.g., Gaucher andParkinson’s diseases) and to examine the effectiveness of pharmacological chaperone treatment. In 2006,his team received a “Thethe use of chaperones for the treatment of Parkinson’s disease and now several molecules are inadvanced preclinical development for PD. In 2010, he received a grant froDiscovery Foundation which is focused on demonstrating in vivo proofganglioside catabolism as a potential therapy for Alzheimer’s disease. Additionally, his team is currentlydeveloping presenilinAlzheimer’s disease.


Brandon A. Wustman

Amicus Therapeutics

Many neurodegenerative disorders are characterized by the accumulation and aggregation of amyloidpeptide (Aβ), hyperphosphorylated tau, and αsystem as a central cause of these disorders, supported by the genetic link between Parkinson’s diseaseand the lysosomal storage disorder (LSD) Gaucher disease. As a result, we have investigatelinks between other LSDs and neurodegenerative disorders (e.g., Alzheimer’s disease). Sinceintraneuronal Aβ accumulation has been observed in a mouse model of Sandhoff disease and gangliosides have been shown to promote Aβ oligomerization in viand hippocampus) from individuals with GM1 and GM2 gangliosidoses (GM1 gangliosidosis, Taydisease, and Sandoff disease; n = 8), Alzheimer’s disease (AD, n=2) and ageobserved obvious accumulation of intraneuronal Aβ, gangliosideimmunoreactivity, and αAmyloid plaques and neurofibrillary tangles were observed inproposed to act as a nucleation seed for Aβ oligomerization, and is thus thought to represent a preaggregate in AD.


Wustman

Brandon Wustman, PhD, heads the Preclinical Biology department at AmicusTherapeuticsthe treatment of diseases associated with the misfolding and mistrafficking of proteins. Dr.Wustman received his PhD in biology from Michigan Technological University in 1998 andwas awarded a postdoctoral fellowship from the Alexander Von Humboldt Society wherehe continued his research on protein folding and trafficking at the University of Cologne inCologne, Germany. In 2000, Dr. Wustman joined Dr. John Evan’s laboratory in thechemistry department at New York University to study protein folding at the molecular level


Since joining Amicus in 2002, he has applied a wide variety of analytical, biotechniques to 1) better understand the cellular pathologies of various lysosomal storage disorders and theirrelationship to other more common neurodegenerative disorders and 2) to study the effects ofpharmacological chaperonediscovery efforts and mechanismthat entered clinical trials as potential treatments for Fabry (Phase 3(Phase 2) diseases. Additionally, his lab has been exploring how impaired glycosphingolipid/gangliosidemetabolism may contribute to neurodegeneration and developing pharmacological chaperones that canmodulate lipid metabolism as a approach to treating neurodegenerative diseases such as Parkinson’s andAlzheimer’s. We have identified several animal models with impaired glycosphingolipid catabolism that

and AD-like pathologies and some of these animals are being usglycosphingolipid metabolism disorders and various neurodegenerative diseases (e.g., Gaucher andParkinson’s diseases) and to examine the effectiveness of pharmacological chaperone treatment. In 2006,his team received a “Therapeutics Initiative Grant” from the Michael J. Fox Foundation to further investigatethe use of chaperones for the treatment of Parkinson’s disease and now several molecules are inadvanced preclinical development for PD. In 2010, he received a grant froDiscovery Foundation which is focused on demonstrating in vivo proofganglioside catabolism as a potential therapy for Alzheimer’s disease. Additionally, his team is currentlydeveloping presenilin-targetedAlzheimer’s disease.


Brandon A. Wustman1, Sam Gandy

Amicus Therapeutics, Inc

Many neurodegenerative disorders are characterized by the accumulation and aggregation of amyloid, hyperphosphorylated tau, and α

system as a central cause of these disorders, supported by the genetic link between Parkinson’s diseaseand the lysosomal storage disorder (LSD) Gaucher disease. As a result, we have investigatelinks between other LSDs and neurodegenerative disorders (e.g., Alzheimer’s disease). Sinceintraneuronal Aβ accumulation has been observed in a mouse model of Sandhoff disease and gangliosides have been shown to promote Aβ oligomerization in viand hippocampus) from individuals with GM1 and GM2 gangliosidoses (GM1 gangliosidosis, Taydisease, and Sandoff disease; n = 8), Alzheimer’s disease (AD, n=2) and age

ed obvious accumulation of intraneuronal Aβ, gangliosideimmunoreactivity, and α-synuclein in all of the gangliosidosis brains, but not in ageAmyloid plaques and neurofibrillary tangles were observed inproposed to act as a nucleation seed for Aβ oligomerization, and is thus thought to represent a preaggregate in AD.


Wustman, PhD, Amicus Therapeutics

Brandon Wustman, PhD, heads the Preclinical Biology department at AmicusTherapeutics, Inc. and specializes in the development of pharmacological chaperones forthe treatment of diseases associated with the misfolding and mistrafficking of proteins. Dr.Wustman received his PhD in biology from Michigan Technological University in 1998 and

warded a postdoctoral fellowship from the Alexander Von Humboldt Society wherehe continued his research on protein folding and trafficking at the University of Cologne inCologne, Germany. In 2000, Dr. Wustman joined Dr. John Evan’s laboratory in the

istry department at New York University to study protein folding at the molecular levelusing a combination of NMR spectroscopy, MALDI/TOF and molecular modeling techniques.

Since joining Amicus in 2002, he has applied a wide variety of analytical, biotechniques to 1) better understand the cellular pathologies of various lysosomal storage disorders and theirrelationship to other more common neurodegenerative disorders and 2) to study the effects ofpharmacological chaperones on protein folding, trafficking and cellular stress pathways. His labs’ drugdiscovery efforts and mechanism-of-action studies have contributed to the development of three therapiesthat entered clinical trials as potential treatments for Fabry (Phase 3(Phase 2) diseases. Additionally, his lab has been exploring how impaired glycosphingolipid/gangliosidemetabolism may contribute to neurodegeneration and developing pharmacological chaperones that can

sm as a approach to treating neurodegenerative diseases such as Parkinson’s andAlzheimer’s. We have identified several animal models with impaired glycosphingolipid catabolism that

like pathologies and some of these animals are being usglycosphingolipid metabolism disorders and various neurodegenerative diseases (e.g., Gaucher andParkinson’s diseases) and to examine the effectiveness of pharmacological chaperone treatment. In 2006,

rapeutics Initiative Grant” from the Michael J. Fox Foundation to further investigatethe use of chaperones for the treatment of Parkinson’s disease and now several molecules are inadvanced preclinical development for PD. In 2010, he received a grant froDiscovery Foundation which is focused on demonstrating in vivo proofganglioside catabolism as a potential therapy for Alzheimer’s disease. Additionally, his team is currently

targeted pharmacological chaperones for the treatment of early onset familial


Sam Gandy2

Inc., La Jolla, CA

Many neurodegenerative disorders are characterized by the accumulation and aggregation of amyloid, hyperphosphorylated tau, and α


ed obvious accumulation of intraneuronal Aβ, gangliosidesynuclein in all of the gangliosidosis brains, but not in age

Amyloid plaques and neurofibrillary tangles were observed inproposed to act as a nucleation seed for Aβ oligomerization, and is thus thought to represent a pre

Amicus Therapeutics

Brandon Wustman, PhD, heads the Preclinical Biology department at Amicusand specializes in the development of pharmacological chaperones for

the treatment of diseases associated with the misfolding and mistrafficking of proteins. Dr.Wustman received his PhD in biology from Michigan Technological University in 1998 and



Since joining Amicus in 2002, he has applied a wide variety of analytical, biotechniques to 1) better understand the cellular pathologies of various lysosomal storage disorders and theirrelationship to other more common neurodegenerative disorders and 2) to study the effects of

s on protein folding, trafficking and cellular stress pathways. His labs’ drugaction studies have contributed to the development of three therapies

that entered clinical trials as potential treatments for Fabry (Phase 3(Phase 2) diseases. Additionally, his lab has been exploring how impaired glycosphingolipid/gangliosidemetabolism may contribute to neurodegeneration and developing pharmacological chaperones that can




pharmacological chaperones for the treatment of early onset familial

Modulation of Ganglioside Catabolism Using Pharmacological Chaperones: A Novel Therapeutic

, La Jolla, CA; 2Mount Sinai School of Medicine New York, NY

Many neurodegenerative disorders are characterized by the accumulation and aggregation of amyloid, hyperphosphorylated tau, and α-synuclein. Mounting evidence points to a deficient lysosomal




Amicus Therapeutics







that entered clinical trials as potential treatments for Fabry (Phase 3(Phase 2) diseases. Additionally, his lab has been exploring how impaired glycosphingolipid/gangliosidemetabolism may contribute to neurodegeneration and developing pharmacological chaperones that can






Mount Sinai School of Medicine New York, NY

Many neurodegenerative disorders are characterized by the accumulation and aggregation of amyloidsynuclein. Mounting evidence points to a deficient lysosomal

system as a central cause of these disorders, supported by the genetic link between Parkinson’s diseaseand the lysosomal storage disorder (LSD) Gaucher disease. As a result, we have investigatelinks between other LSDs and neurodegenerative disorders (e.g., Alzheimer’s disease). Sinceintraneuronal Aβ accumulation has been observed in a mouse model of Sandhoff disease and gangliosides have been shown to promote Aβ oligomerization in vitro, we analyzed postand hippocampus) from individuals with GM1 and GM2 gangliosidoses (GM1 gangliosidosis, Taydisease, and Sandoff disease; n = 8), Alzheimer’s disease (AD, n=2) and age



Amicus Therapeutics, Inc.







that entered clinical trials as potential treatments for Fabry (Phase 3), Gaucher (Phase 2) and Pompe(Phase 2) diseases. Additionally, his lab has been exploring how impaired glycosphingolipid/gangliosidemetabolism may contribute to neurodegeneration and developing pharmacological chaperones that can








system as a central cause of these disorders, supported by the genetic link between Parkinson’s diseaseand the lysosomal storage disorder (LSD) Gaucher disease. As a result, we have investigatelinks between other LSDs and neurodegenerative disorders (e.g., Alzheimer’s disease). Sinceintraneuronal Aβ accumulation has been observed in a mouse model of Sandhoff disease and gangliosides

tro, we analyzed postand hippocampus) from individuals with GM1 and GM2 gangliosidoses (GM1 gangliosidosis, Taydisease, and Sandoff disease; n = 8), Alzheimer’s disease (AD, n=2) and age


Amyloid plaques and neurofibrillary tangles were observed in the AD brains as expected. GAβ has been proposed to act as a nucleation seed for Aβ oligomerization, and is thus thought to represent a pre





Since joining Amicus in 2002, he has applied a wide variety of analytical, biochemical and cell biologicaltechniques to 1) better understand the cellular pathologies of various lysosomal storage disorders and theirrelationship to other more common neurodegenerative disorders and 2) to study the effects of


), Gaucher (Phase 2) and Pompe(Phase 2) diseases. Additionally, his lab has been exploring how impaired glycosphingolipid/gangliosidemetabolism may contribute to neurodegeneration and developing pharmacological chaperones that can


like pathologies and some of these animals are being used to study the links betweenglycosphingolipid metabolism disorders and various neurodegenerative diseases (e.g., Gaucher andParkinson’s diseases) and to examine the effectiveness of pharmacological chaperone treatment. In 2006,

rapeutics Initiative Grant” from the Michael J. Fox Foundation to further investigatethe use of chaperones for the treatment of Parkinson’s disease and now several molecules are inadvanced preclinical development for PD. In 2010, he received a grant from the Alzheimer’s DrugDiscovery Foundation which is focused on demonstrating in vivo proof-of-concept for increasingganglioside catabolism as a potential therapy for Alzheimer’s disease. Additionally, his team is currently






tro, we analyzed post-mortem human brains (cortexand hippocampus) from individuals with GM1 and GM2 gangliosidoses (GM1 gangliosidosis, Taydisease, and Sandoff disease; n = 8), Alzheimer’s disease (AD, n=2) and age-matched controls (n=5). We

ed obvious accumulation of intraneuronal Aβ, ganglioside-bound Aβ (GAβ), phosphosynuclein in all of the gangliosidosis brains, but not in age-matched control brains.

the AD brains as expected. GAβ has been proposed to act as a nucleation seed for Aβ oligomerization, and is thus thought to represent a pre





chemical and cell biologicaltechniques to 1) better understand the cellular pathologies of various lysosomal storage disorders and theirrelationship to other more common neurodegenerative disorders and 2) to study the effects of




ed to study the links betweenglycosphingolipid metabolism disorders and various neurodegenerative diseases (e.g., Gaucher andParkinson’s diseases) and to examine the effectiveness of pharmacological chaperone treatment. In 2006,

rapeutics Initiative Grant” from the Michael J. Fox Foundation to further investigatethe use of chaperones for the treatment of Parkinson’s disease and now several molecules are in

m the Alzheimer’s Drugconcept for increasing

ganglioside catabolism as a potential therapy for Alzheimer’s disease. Additionally, his team is currentlypharmacological chaperones for the treatment of early onset familial





mortem human brains (cortexand hippocampus) from individuals with GM1 and GM2 gangliosidoses (GM1 gangliosidosis, Tay

matched controls (n=5). Webound Aβ (GAβ), phospho

matched control brains.the AD brains as expected. GAβ has been

proposed to act as a nucleation seed for Aβ oligomerization, and is thus thought to represent a pre

31




istry department at New York University to study protein folding at the molecular level










Many neurodegenerative disorders are characterized by the accumulation and aggregation of amyloid-β synuclein. Mounting evidence points to a deficient lysosomal

system as a central cause of these disorders, supported by the genetic link between Parkinson’s diseaseand the lysosomal storage disorder (LSD) Gaucher disease. As a result, we have investigated possiblelinks between other LSDs and neurodegenerative disorders (e.g., Alzheimer’s disease). Sinceintraneuronal Aβ accumulation has been observed in a mouse model of Sandhoff disease and gangliosides

mortem human brains (cortexand hippocampus) from individuals with GM1 and GM2 gangliosidoses (GM1 gangliosidosis, Tay-Sachs

matched controls (n=5). Webound Aβ (GAβ), phospho-tau


proposed to act as a nucleation seed for Aβ oligomerization, and is thus thought to represent a pre-fibrillar




istry department at New York University to study protein folding at the molecular level









β synuclein. Mounting evidence points to a deficient lysosomal

system as a central cause of these disorders, supported by the genetic link between Parkinson’s diseased possible

links between other LSDs and neurodegenerative disorders (e.g., Alzheimer’s disease). Sinceintraneuronal Aβ accumulation has been observed in a mouse model of Sandhoff disease and gangliosides

mortem human brains (cortexSachs

matched controls (n=5). Wetau


fibrillar

32

Our preliminary studies also suggest that modulating ganglioside metabolism can alter APP metabolism,providing a novel means by which to decrease Aβ generation and increase sAPPα shedding without directly inhibiting γ- or β-secretase activity. We have previously shown that small molecules can be used to selectively stabilize and increase enzymatic activity of endogenous wild-type lysosomal hydrolases. Thus,we believe this research may lead to the development of new, disease-modifying therapies for Alzheimer’sdisease, as well as the rarer LSDs (e.g., Sandhoff, Tay-Sachs) that share a common pharmaceuticalprotein target.


Gabriela Chiosis

training at Columbia University in New York and has joined Memorial Sloan1998. The Chiosis Laboratory investigates the significance of modulating molecular chaperones in diseasetreatment.Hsp90 in regulating the stability and function of aberrant protein driving the neurodegenerative phenotypein tauopathies. Hsp90 inhibitors discovered by the labpurine

Heat Shock Protein 90 in Neurodegenerative Diseases

Gabriela Chiosis

Memorial Sloan Kettering Cancer

Hsp90 is a molecular chaperone with important roles in regulating pathogenic transformation. In addition toits wellHsp90 inovercurrent knowledge on Hsp90 in neurodegeneration antargeting by small molecule Hsp90 inhibitors of “pathogenic” Hsp90 species, such as characteristic ofcancer cells and of neurons undergoing the neurodegenerative transformation.


Gabriela Chiosis

training at Columbia University in New York and has joined Memorial Sloan1998. The Chiosis Laboratory investigates the significance of modulating molecular chaperones in diseasetreatment. In this respect, it has developed pharmacological tools instrumental in defining the roles ofHsp90 in regulating the stability and function of aberrant protein driving the neurodegenerative phenotypein tauopathies. Hsp90 inhibitors discovered by the labpurine-scaffold Hsp90 inhibitors currently in clinical evaluation in patients with advanced cancers.


Gabriela Chiosis


Hsp90 is a molecular chaperone with important roles in regulating pathogenic transformation. In addition toits well-characterized functions in malignancy, recent evidence from several laboratories suggests a role forHsp90 in maintaining the functional stability of neuronal proteins of aberrant capacity, whether mutated orover-activated, allowing and sustaining the accumulation of toxic aggregates. This talk will summarize ourcurrent knowledge on Hsp90 in neurodegeneration antargeting by small molecule Hsp90 inhibitors of “pathogenic” Hsp90 species, such as characteristic ofcancer cells and of neurons undergoing the neurodegenerative transformation.


Gabriela Chiosis, PhD,

Dr. Gabriela Chiosis is a Principal Investigator and an Associate Member in the Program inMolecular Pharmacology and Chemistry at SloanAttending in the Department of Medicine of Memorial Hospital for Cancer & Allied Diseases,New York. She is also a faculty in several biomedical graduate programs such as theProgram in Pharmacology, Weill Graduate School of Medthe Tri-Institutional Training Program in Chemical Biology, SloanCancer Center, Cornell University and The Rockefeller University and the Cancer BiologyProgram of the Gerstner Sloan

training at Columbia University in New York and has joined Memorial Sloan1998. The Chiosis Laboratory investigates the significance of modulating molecular chaperones in disease

In this respect, it has developed pharmacological tools instrumental in defining the roles ofHsp90 in regulating the stability and function of aberrant protein driving the neurodegenerative phenotypein tauopathies. Hsp90 inhibitors discovered by the lab

scaffold Hsp90 inhibitors currently in clinical evaluation in patients with advanced cancers.


Gabriela Chiosis


Hsp90 is a molecular chaperone with important roles in regulating pathogenic transformation. In addition tocharacterized functions in malignancy, recent evidence from several laboratories suggests a role for

maintaining the functional stability of neuronal proteins of aberrant capacity, whether mutated oractivated, allowing and sustaining the accumulation of toxic aggregates. This talk will summarize our

current knowledge on Hsp90 in neurodegeneration antargeting by small molecule Hsp90 inhibitors of “pathogenic” Hsp90 species, such as characteristic ofcancer cells and of neurons undergoing the neurodegenerative transformation.


, PhD, Memorial Sloan Kettering Cancer Center

Dr. Gabriela Chiosis is a Principal Investigator and an Associate Member in the Program inMolecular Pharmacology and Chemistry at SloanAttending in the Department of Medicine of Memorial Hospital for Cancer & Allied Diseases,New York. She is also a faculty in several biomedical graduate programs such as theProgram in Pharmacology, Weill Graduate School of Med

Institutional Training Program in Chemical Biology, SloanCancer Center, Cornell University and The Rockefeller University and the Cancer BiologyProgram of the Gerstner Sloan





Memorial Sloan Kettering Cancer Center






Institutional Training Program in Chemical Biology, SloanCancer Center, Cornell University and The Rockefeller University and the Cancer BiologyProgram of the Gerstner Sloan





Center, New York, NY






Institutional Training Program in Chemical Biology, SloanCancer Center, Cornell University and The Rockefeller University and the Cancer BiologyProgram of the Gerstner Sloan-Kettering Gra


In this respect, it has developed pharmacological tools instrumental in defining the roles ofHsp90 in regulating the stability and function of aberrant protein driving the neurodegenerative phenotypein tauopathies. Hsp90 inhibitors discovered by the lab are the platform for the development of several



, New York, NY



current knowledge on Hsp90 in neurodegeneration and will discuss the mechanisms behind selectivetargeting by small molecule Hsp90 inhibitors of “pathogenic” Hsp90 species, such as characteristic ofcancer cells and of neurons undergoing the neurodegenerative transformation.


Dr. Gabriela Chiosis is a Principal Investigator and an Associate Member in the Program inMolecular Pharmacology and Chemistry at Sloan-KetteringAttending in the Department of Medicine of Memorial Hospital for Cancer & Allied Diseases,New York. She is also a faculty in several biomedical graduate programs such as theProgram in Pharmacology, Weill Graduate School of Med

Institutional Training Program in Chemical Biology, SloanCancer Center, Cornell University and The Rockefeller University and the Cancer Biology

Kettering Graduate School. She received her graduatetraining at Columbia University in New York and has joined Memorial Sloan1998. The Chiosis Laboratory investigates the significance of modulating molecular chaperones in disease

In this respect, it has developed pharmacological tools instrumental in defining the roles ofHsp90 in regulating the stability and function of aberrant protein driving the neurodegenerative phenotype

are the platform for the development of severalscaffold Hsp90 inhibitors currently in clinical evaluation in patients with advanced cancers.



d will discuss the mechanisms behind selectivetargeting by small molecule Hsp90 inhibitors of “pathogenic” Hsp90 species, such as characteristic ofcancer cells and of neurons undergoing the neurodegenerative transformation.


Dr. Gabriela Chiosis is a Principal Investigator and an Associate Member in the Program inKettering Institute, and an Associate

Attending in the Department of Medicine of Memorial Hospital for Cancer & Allied Diseases,New York. She is also a faculty in several biomedical graduate programs such as theProgram in Pharmacology, Weill Graduate School of Medical Sciences, Cornell University,

Institutional Training Program in Chemical Biology, SloanCancer Center, Cornell University and The Rockefeller University and the Cancer Biology

duate School. She received her graduatetraining at Columbia University in New York and has joined Memorial Sloan-Kettering Cancer Center in1998. The Chiosis Laboratory investigates the significance of modulating molecular chaperones in disease





d will discuss the mechanisms behind selectivetargeting by small molecule Hsp90 inhibitors of “pathogenic” Hsp90 species, such as characteristic ofcancer cells and of neurons undergoing the neurodegenerative transformation.

Dr. Gabriela Chiosis is a Principal Investigator and an Associate Member in the Program inInstitute, and an Associate

Attending in the Department of Medicine of Memorial Hospital for Cancer & Allied Diseases,New York. She is also a faculty in several biomedical graduate programs such as the

ical Sciences, Cornell University,Institutional Training Program in Chemical Biology, Sloan-Kettering Institute for

Cancer Center, Cornell University and The Rockefeller University and the Cancer Biologyduate School. She received her graduate

Kettering Cancer Center in1998. The Chiosis Laboratory investigates the significance of modulating molecular chaperones in disease





d will discuss the mechanisms behind selectivetargeting by small molecule Hsp90 inhibitors of “pathogenic” Hsp90 species, such as characteristic of

33



ical Sciences, Cornell University,Kettering Institute for










ical Sciences, Cornell University,Kettering Institute for




are the platform for the development of several




34

CLOSING REMARKSDiana

dissertation research, Dr.was an active member of the Penn Biotechnology Group. Dr. Shineman received a BA in Biology with aNutrition concentration from Cornell University, where she was named a HoResearch Scholar. She is also a member of the Society for Neuroscience and an author on numerouspeer

Dr. Shineman will present a posterBest Practices for Preclinical Animal Studies.

CLOSING REMARKSDiana Shineman, PhD

dissertation research, Dr.was an active member of the Penn Biotechnology Group. Dr. Shineman received a BA in Biology with aNutrition concentration from Cornell University, where she was named a HoResearch Scholar. She is also a member of the Society for Neuroscience and an author on numerouspeer-reviewed publications.


CLOSING REMARKSShineman, PhD

Diana Shineman,Discovery Foundation, where she is responsible for developing and managing all aspectsof the Foundation’s drug diCell and Molecular Biology from the University of Pennsylvania (Penn). At Penn’srenowned Center for Neurodegenerative Disease Research led by Drs. Virginia Lee andJohn Trojanowski, she studiedin Alzheimer’s disease. Dr. Shineman also worked with the Center’s Drug DiscoveryGroup to perform high

dissertation research, Dr.was an active member of the Penn Biotechnology Group. Dr. Shineman received a BA in Biology with aNutrition concentration from Cornell University, where she was named a HoResearch Scholar. She is also a member of the Society for Neuroscience and an author on numerous

reviewed publications.


CLOSING REMARKSShineman, PhD, Alzheimer’s Drug Discovery Foundation

Diana Shineman, PhD, is Assistant Director,Discovery Foundation, where she is responsible for developing and managing all aspectsof the Foundation’s drug diCell and Molecular Biology from the University of Pennsylvania (Penn). At Penn’srenowned Center for Neurodegenerative Disease Research led by Drs. Virginia Lee andJohn Trojanowski, she studiedin Alzheimer’s disease. Dr. Shineman also worked with the Center’s Drug DiscoveryGroup to perform high

dissertation research, Dr. Shineman was as an Editorial Intern for the Journal of Clinical Investigation andwas an active member of the Penn Biotechnology Group. Dr. Shineman received a BA in Biology with aNutrition concentration from Cornell University, where she was named a HoResearch Scholar. She is also a member of the Society for Neuroscience and an author on numerous

reviewed publications.

Dr. Shineman will present a poster at this meetingBest Practices for Preclinical Animal Studies.


PhD, is Assistant Director,Discovery Foundation, where she is responsible for developing and managing all aspectsof the Foundation’s drug discovery research programs. Dr. Shineman earned her PhD inCell and Molecular Biology from the University of Pennsylvania (Penn). At Penn’srenowned Center for Neurodegenerative Disease Research led by Drs. Virginia Lee andJohn Trojanowski, she studied signal transduction pathways that alter amyloid generationin Alzheimer’s disease. Dr. Shineman also worked with the Center’s Drug DiscoveryGroup to perform high-throughput screening using cell

Shineman was as an Editorial Intern for the Journal of Clinical Investigation andwas an active member of the Penn Biotechnology Group. Dr. Shineman received a BA in Biology with aNutrition concentration from Cornell University, where she was named a HoResearch Scholar. She is also a member of the Society for Neuroscience and an author on numerous

at this meetingBest Practices for Preclinical Animal Studies. An abstract is included in the Poster Presentation handout.


PhD, is Assistant Director,Discovery Foundation, where she is responsible for developing and managing all aspects

scovery research programs. Dr. Shineman earned her PhD inCell and Molecular Biology from the University of Pennsylvania (Penn). At Penn’srenowned Center for Neurodegenerative Disease Research led by Drs. Virginia Lee and

signal transduction pathways that alter amyloid generationin Alzheimer’s disease. Dr. Shineman also worked with the Center’s Drug Discovery

throughput screening using cellShineman was as an Editorial Intern for the Journal of Clinical Investigation and

was an active member of the Penn Biotechnology Group. Dr. Shineman received a BA in Biology with aNutrition concentration from Cornell University, where she was named a HoResearch Scholar. She is also a member of the Society for Neuroscience and an author on numerous

at this meeting on Accelerating Drug Discovery for Alzheimer’s DiseAn abstract is included in the Poster Presentation handout.


PhD, is Assistant Director, Scientific Affairs at the Alzheimer’s DrugDiscovery Foundation, where she is responsible for developing and managing all aspects



throughput screening using cellShineman was as an Editorial Intern for the Journal of Clinical Investigation and

was an active member of the Penn Biotechnology Group. Dr. Shineman received a BA in Biology with aNutrition concentration from Cornell University, where she was named a HoResearch Scholar. She is also a member of the Society for Neuroscience and an author on numerous

Accelerating Drug Discovery for Alzheimer’s DiseAn abstract is included in the Poster Presentation handout.


Scientific Affairs at the Alzheimer’s DrugDiscovery Foundation, where she is responsible for developing and managing all aspects



throughput screening using cell-based assays. In addition to herShineman was as an Editorial Intern for the Journal of Clinical Investigation and

was an active member of the Penn Biotechnology Group. Dr. Shineman received a BA in Biology with aNutrition concentration from Cornell University, where she was named a Howard Hughes UndergraduateResearch Scholar. She is also a member of the Society for Neuroscience and an author on numerous





based assays. In addition to herShineman was as an Editorial Intern for the Journal of Clinical Investigation and

was an active member of the Penn Biotechnology Group. Dr. Shineman received a BA in Biology with award Hughes Undergraduate

Research Scholar. She is also a member of the Society for Neuroscience and an author on numerous








Accelerating Drug Discovery for Alzheimer’s Disease:An abstract is included in the Poster Presentation handout.







ase:


PLENARY SPEAKERRyan

Enhancing CNS Uptake of Biologics through Molecular Engineering

Ryan

Genentech

Utilizing receptorexplored for several decades as a mechanism to increase protein delivery to the brain. Nevertheless, manyhave discovered that antibodies targeting RMaccumulate in CNS vasculature and fail to cross the BBB in appreciable concentrations. We havediscovered that reducing the affinity of an antibody for the TfR enhances RMT of the antiacrosantibodies that bind with high affinity to TfR remain associated with the BBB, whereas lowerTfR antibody variants are released from the BBB intdosing. We designed a bispecific antibody that binds with low affinity to TfR and with high affinity to theenzyme bpeptides including those associated with Alzheimer’s disease. Compared to monospecific antiantibody, the bispecific antibody accumulated in the mouse brain and led to a greater reduction in brainAbeta after a single systemic dose. TfRmay enhance its potency as an anti


PLENARY SPEAKERRyan J. Watts


Ryan J. Watts

Genentech, South

Utilizing receptorexplored for several decades as a mechanism to increase protein delivery to the brain. Nevertheless, manyhave discovered that antibodies targeting RMaccumulate in CNS vasculature and fail to cross the BBB in appreciable concentrations. We havediscovered that reducing the affinity of an antibody for the TfR enhances RMT of the antiacross the BBB into the mouse brain where it reaches therapeutically relevant concentrations. Antiantibodies that bind with high affinity to TfR remain associated with the BBB, whereas lowerTfR antibody variants are released from the BBB intdosing. We designed a bispecific antibody that binds with low affinity to TfR and with high affinity to theenzyme b-secretase (BACE1), which processes amyloid precursor protein into amyloidpeptides including those associated with Alzheimer’s disease. Compared to monospecific antiantibody, the bispecific antibody accumulated in the mouse brain and led to a greater reduction in brainAbeta after a single systemic dose. TfRmay enhance its potency as an anti


PLENARY SPEAKERWatts, PhD,

Dr. Ryan J. Watts is an Associate Director and Head of theGenentech. He received hisdevelopment. Dr. Watts joinedbiology, and morebloodbrainUtah with a


Watts

South San Francisco, CA

Utilizing receptor-mediated transcytosis (RMT) pathways to cross the bloodexplored for several decades as a mechanism to increase protein delivery to the brain. Nevertheless, manyhave discovered that antibodies targeting RMaccumulate in CNS vasculature and fail to cross the BBB in appreciable concentrations. We havediscovered that reducing the affinity of an antibody for the TfR enhances RMT of the anti

s the BBB into the mouse brain where it reaches therapeutically relevant concentrations. Antiantibodies that bind with high affinity to TfR remain associated with the BBB, whereas lowerTfR antibody variants are released from the BBB intdosing. We designed a bispecific antibody that binds with low affinity to TfR and with high affinity to the

secretase (BACE1), which processes amyloid precursor protein into amyloidpeptides including those associated with Alzheimer’s disease. Compared to monospecific antiantibody, the bispecific antibody accumulated in the mouse brain and led to a greater reduction in brainAbeta after a single systemic dose. TfRmay enhance its potency as an anti


PLENARY SPEAKER, PhD, Genentech

Dr. Ryan J. Watts is an Associate Director and Head of theGenentech. He received hisdevelopment. Dr. Watts joinedbiology, and morebloodbrain barrier. Dr. Watts received his undergraduate training from theUtah with a BS in Biology.


San Francisco, CA

mediated transcytosis (RMT) pathways to cross the bloodexplored for several decades as a mechanism to increase protein delivery to the brain. Nevertheless, manyhave discovered that antibodies targeting RMaccumulate in CNS vasculature and fail to cross the BBB in appreciable concentrations. We havediscovered that reducing the affinity of an antibody for the TfR enhances RMT of the anti


secretase (BACE1), which processes amyloid precursor protein into amyloidpeptides including those associated with Alzheimer’s disease. Compared to monospecific antiantibody, the bispecific antibody accumulated in the mouse brain and led to a greater reduction in brainAbeta after a single systemic dose. TfRmay enhance its potency as an anti-BACE1 therapy for treating Alzheimer’s disease.

Genentech

Dr. Ryan J. Watts is an Associate Director and Head of theGenentech. He received his PhDdevelopment. Dr. Watts joined Genentech in 2004 to develop therapies targeting vascular

recently initiated research programs on neurbarrier. Dr. Watts received his undergraduate training from the

in Biology.


San Francisco, CA

mediated transcytosis (RMT) pathways to cross the bloodexplored for several decades as a mechanism to increase protein delivery to the brain. Nevertheless, manyhave discovered that antibodies targeting RMaccumulate in CNS vasculature and fail to cross the BBB in appreciable concentrations. We havediscovered that reducing the affinity of an antibody for the TfR enhances RMT of the anti


secretase (BACE1), which processes amyloid precursor protein into amyloidpeptides including those associated with Alzheimer’s disease. Compared to monospecific antiantibody, the bispecific antibody accumulated in the mouse brain and led to a greater reduction in brainAbeta after a single systemic dose. TfR-facilitated transcytosis of this bispecific antibody across the BBB

BACE1 therapy for treating Alzheimer’s disease.

Dr. Ryan J. Watts is an Associate Director and Head of thePhD from StanfordGenentech in 2004 to develop therapies targeting vascular

recently initiated research programs on neurbarrier. Dr. Watts received his undergraduate training from the


mediated transcytosis (RMT) pathways to cross the bloodexplored for several decades as a mechanism to increase protein delivery to the brain. Nevertheless, manyhave discovered that antibodies targeting RMT pathways, particularly transferrin receptor (TfR),accumulate in CNS vasculature and fail to cross the BBB in appreciable concentrations. We havediscovered that reducing the affinity of an antibody for the TfR enhances RMT of the anti

s the BBB into the mouse brain where it reaches therapeutically relevant concentrations. Antiantibodies that bind with high affinity to TfR remain associated with the BBB, whereas lowerTfR antibody variants are released from the BBB into the brain and show a broad distribution 24 hours afterdosing. We designed a bispecific antibody that binds with low affinity to TfR and with high affinity to the

secretase (BACE1), which processes amyloid precursor protein into amyloidpeptides including those associated with Alzheimer’s disease. Compared to monospecific antiantibody, the bispecific antibody accumulated in the mouse brain and led to a greater reduction in brain

ted transcytosis of this bispecific antibody across the BBBBACE1 therapy for treating Alzheimer’s disease.

Dr. Ryan J. Watts is an Associate Director and Head of thefrom Stanford University studying nervous system

Genentech in 2004 to develop therapies targeting vascularrecently initiated research programs on neur

barrier. Dr. Watts received his undergraduate training from the


mediated transcytosis (RMT) pathways to cross the bloodexplored for several decades as a mechanism to increase protein delivery to the brain. Nevertheless, many

T pathways, particularly transferrin receptor (TfR),accumulate in CNS vasculature and fail to cross the BBB in appreciable concentrations. We havediscovered that reducing the affinity of an antibody for the TfR enhances RMT of the anti

s the BBB into the mouse brain where it reaches therapeutically relevant concentrations. Antiantibodies that bind with high affinity to TfR remain associated with the BBB, whereas lower

o the brain and show a broad distribution 24 hours afterdosing. We designed a bispecific antibody that binds with low affinity to TfR and with high affinity to the



Dr. Ryan J. Watts is an Associate Director and Head of the Neurodegeneration Labs atUniversity studying nervous system

Genentech in 2004 to develop therapies targeting vascularrecently initiated research programs on neurodegeneration and the

barrier. Dr. Watts received his undergraduate training from the


mediated transcytosis (RMT) pathways to cross the blood-brain barrier (BBB) has beenexplored for several decades as a mechanism to increase protein delivery to the brain. Nevertheless, many

T pathways, particularly transferrin receptor (TfR),accumulate in CNS vasculature and fail to cross the BBB in appreciable concentrations. We havediscovered that reducing the affinity of an antibody for the TfR enhances RMT of the anti

s the BBB into the mouse brain where it reaches therapeutically relevant concentrations. Antiantibodies that bind with high affinity to TfR remain associated with the BBB, whereas lower




Neurodegeneration Labs atUniversity studying nervous system

Genentech in 2004 to develop therapies targeting vascularodegeneration and the

barrier. Dr. Watts received his undergraduate training from the University of

brain barrier (BBB) has beenexplored for several decades as a mechanism to increase protein delivery to the brain. Nevertheless, many

T pathways, particularly transferrin receptor (TfR),accumulate in CNS vasculature and fail to cross the BBB in appreciable concentrations. We havediscovered that reducing the affinity of an antibody for the TfR enhances RMT of the anti-TfR antibody

s the BBB into the mouse brain where it reaches therapeutically relevant concentrations. Antiantibodies that bind with high affinity to TfR remain associated with the BBB, whereas lower-affinity anti


secretase (BACE1), which processes amyloid precursor protein into amyloid-beta (Abpeptides including those associated with Alzheimer’s disease. Compared to monospecific antiantibody, the bispecific antibody accumulated in the mouse brain and led to a greater reduction in brain


35



University of


T pathways, particularly transferrin receptor (TfR),accumulate in CNS vasculature and fail to cross the BBB in appreciable concentrations. We have

TfR antibodys the BBB into the mouse brain where it reaches therapeutically relevant concentrations. Anti-TfR

affinity anti-o the brain and show a broad distribution 24 hours after

dosing. We designed a bispecific antibody that binds with low affinity to TfR and with high affinity to thebeta (Abeta)

peptides including those associated with Alzheimer’s disease. Compared to monospecific anti-BACE1antibody, the bispecific antibody accumulated in the mouse brain and led to a greater reduction in brain

ted transcytosis of this bispecific antibody across the BBB



University of


T pathways, particularly transferrin receptor (TfR),accumulate in CNS vasculature and fail to cross the BBB in appreciable concentrations. We have

TfR antibodyTfR


eta)BACE1

antibody, the bispecific antibody accumulated in the mouse brain and led to a greater reduction in brainted transcytosis of this bispecific antibody across the BBB

36

III. Neuroprotection and Synaptic EnhancementChair: Howard Fillit, MD, Alzheimer's Drug Discovery Foundation

Tricyclic Pyrone Compounds and Axonal Trafficking Dysfunction in ADEugenia Trushina, PhD, Mayo Clinic College of Medicine

Targeting Neuronal Calcium Signaling to Halt AD-linked Synaptic DysfunctionGrace E. Stutzmann, PhD, Rosalind Franklin University School of Medicine

Klotho Enhances Oligodendrocyte Maturation and MyelinationCarmela R. Abraham, PhD, Boston University School of Medicine

Mapping the Binding Site of HDAC 2 for the Design of Novel HDAC Inhibitors Lacking Zinc BindingGroupPavel A. Petukhov, PhD, University of Illinois at Chicago

Targeting the Neuronal Calcium Sensor (NCS) Protein, VILIP-1, for Cognitive Impairment in CNSDisordersKarl-Heinz Braunewell, PhD, Southern Research Institute

Efficacy of Herbal Extract, Tetramethylpyrazine, for Alzheimer’s DiseaseZhiqun Tan, MD, PhD, University of California, Irvine


Eugenia Trushina

therapeutic approaches, and identification of specific biomarkers useful for early diagnosis andmonitoring/predicting the disease progression. In addition to her ADDF awaof AHAF award

Tricyclic Pyrone Compounds and Axonal Trafficking Dysfunction in AD

Eugenia Trushina

Mayo Clinic College of Medicine

Previously, we demonstrated that small molecules, tricyclic pyronesparticular, TP compounds prevent cell death in celular models of Alzheimer’s Disease (AD) by reducingintracellular accumulation of toxic Aβ oligomers. The lead TP compound, code named CP2, has been shown to eliminamyloid plaques, in 5x familial AD mice following oral or intraperitoneal administration. Preliminarypharmacokinetics and toxicity studies have demonstrated that CPblooddynamics, morphology and function are altered in three transgenic mouse models of familial AD (APP, PS1and APP/involved in the alteration of mitochondrial dynamics early in disease progression prior to the onset ofmemory and neurological phenotypes. Therefore, we tested whetonset and slows the progression of AD in transgenic mice, and improves mitochondrial function. Our datasuggest that longcause toxictrafficking in neurons from embryonic AD mice whose parents were treated with CP2; (5) CP2animals demonstrate significant improvement in memory comparapplication of TP compounds represents a promissing therapeutic approach in the treatment of AD.


Eugenia Trushina

therapeutic approaches, and identification of specific biomarkers useful for early diagnosis andmonitoring/predicting the disease progression. In addition to her ADDF awaof AHAF award


Eugenia Trushina


Previously, we demonstrated that small molecules, tricyclic pyronesparticular, TP compounds prevent cell death in celular models of Alzheimer’s Disease (AD) by reducingintracellular accumulation of toxic Aβ oligomers. The lead TP compound, code named CP2, has been shown to eliminamyloid plaques, in 5x familial AD mice following oral or intraperitoneal administration. Preliminarypharmacokinetics and toxicity studies have demonstrated that CPblood-brain barrier permeability and oral availability. Recently, we have demonstrated that mitochondrialdynamics, morphology and function are altered in three transgenic mouse models of familial AD (APP, PS1and APP/PS1). Moreover, our data demonstrate that nonfibrillar Ainvolved in the alteration of mitochondrial dynamics early in disease progression prior to the onset ofmemory and neurological phenotypes. Therefore, we tested whetonset and slows the progression of AD in transgenic mice, and improves mitochondrial function. Our datasuggest that longcause toxic side effects; (3) does not affect animal ability to breed; (4) CP2 treatment restores Mitotrafficking in neurons from embryonic AD mice whose parents were treated with CP2; (5) CP2animals demonstrate significant improvement in memory comparapplication of TP compounds represents a promissing therapeutic approach in the treatment of AD.


Eugenia Trushina, PhD,

Dr. Trushina is an Assistant Professor in the Department of Neurology at the Mayo ClinicRochester. She received her doctoral degree from Saratov State University in Russia. Dr.Trushina received her postdoctoral training at the Mayo Clinic, Rochester where sheworked with Drs. C. McMurray, R. Pagano and M. McNiven. Dr. Trushina’s laboratory ifocused on the understanding the role that mitochondrial dysfunction plays in multipleneurodegenerative disorders including Huntington’s and Alzheimer’s Diseases. Herresearch interests involve identification of the molecular mechanisms involved in theinhibition of mitochondrial dynamics and function, testing new mitochondria

therapeutic approaches, and identification of specific biomarkers useful for early diagnosis andmonitoring/predicting the disease progression. In addition to her ADDF awaof AHAF award.


Eugenia Trushina


Previously, we demonstrated that small molecules, tricyclic pyronesparticular, TP compounds prevent cell death in celular models of Alzheimer’s Disease (AD) by reducingintracellular accumulation of toxic Aβ oligomers. The lead TP compound, code named CP2, has been shown to eliminate ~80% of cerebral amyloid aggregates, including nonfibrillar Aamyloid plaques, in 5x familial AD mice following oral or intraperitoneal administration. Preliminarypharmacokinetics and toxicity studies have demonstrated that CP

brain barrier permeability and oral availability. Recently, we have demonstrated that mitochondrialdynamics, morphology and function are altered in three transgenic mouse models of familial AD (APP, PS1

PS1). Moreover, our data demonstrate that nonfibrillar Ainvolved in the alteration of mitochondrial dynamics early in disease progression prior to the onset ofmemory and neurological phenotypes. Therefore, we tested whetonset and slows the progression of AD in transgenic mice, and improves mitochondrial function. Our datasuggest that long-term CP2 treatment (up to 12 months) (1) does not alter the development; (2) does not

side effects; (3) does not affect animal ability to breed; (4) CP2 treatment restores Mitotrafficking in neurons from embryonic AD mice whose parents were treated with CP2; (5) CP2animals demonstrate significant improvement in memory comparapplication of TP compounds represents a promissing therapeutic approach in the treatment of AD.


, PhD, Mayo Clinic College of Medicine


therapeutic approaches, and identification of specific biomarkers useful for early diagnosis andmonitoring/predicting the disease progression. In addition to her ADDF awa


Mayo Clinic College of Medicine, Rochester, MN

Previously, we demonstrated that small molecules, tricyclic pyronesparticular, TP compounds prevent cell death in celular models of Alzheimer’s Disease (AD) by reducingintracellular accumulation of toxic Aβ oligomers. The lead TP compound, code named CP2, has been

ate ~80% of cerebral amyloid aggregates, including nonfibrillar Aamyloid plaques, in 5x familial AD mice following oral or intraperitoneal administration. Preliminarypharmacokinetics and toxicity studies have demonstrated that CP


PS1). Moreover, our data demonstrate that nonfibrillar Ainvolved in the alteration of mitochondrial dynamics early in disease progression prior to the onset ofmemory and neurological phenotypes. Therefore, we tested whetonset and slows the progression of AD in transgenic mice, and improves mitochondrial function. Our data

term CP2 treatment (up to 12 months) (1) does not alter the development; (2) does notside effects; (3) does not affect animal ability to breed; (4) CP2 treatment restores Mito

trafficking in neurons from embryonic AD mice whose parents were treated with CP2; (5) CP2animals demonstrate significant improvement in memory comparapplication of TP compounds represents a promissing therapeutic approach in the treatment of AD.





, Rochester, MN





















Previously, we demonstrated that small molecules, tricyclic pyrones (TP), exhibit antiparticular, TP compounds prevent cell death in celular models of Alzheimer’s Disease (AD) by reducingintracellular accumulation of toxic Aβ oligomers. The lead TP compound, code named CP2, has been

ate ~80% of cerebral amyloid aggregates, including nonfibrillar Aamyloid plaques, in 5x familial AD mice following oral or intraperitoneal administration. Preliminarypharmacokinetics and toxicity studies have demonstrated that CP2 is well tolerated and has excellent


PS1). Moreover, our data demonstrate that nonfibrillar A oligomers were the toxic species involved in the alteration of mitochondrial dynamics early in disease progression prior to the onset ofmemory and neurological phenotypes. Therefore, we tested whether administration of CP2 delays theonset and slows the progression of AD in transgenic mice, and improves mitochondrial function. Our data


trafficking in neurons from embryonic AD mice whose parents were treated with CP2; (5) CP2animals demonstrate significant improvement in memory compared to the untreated littermates. Thus,application of TP compounds represents a promissing therapeutic approach in the treatment of AD.



therapeutic approaches, and identification of specific biomarkers useful for early diagnosis andmonitoring/predicting the disease progression. In addition to her ADDF award, Dr. Trushina is a recipient


(TP), exhibit antiparticular, TP compounds prevent cell death in celular models of Alzheimer’s Disease (AD) by reducingintracellular accumulation of toxic Aβ oligomers. The lead TP compound, code named CP2, has been

ate ~80% of cerebral amyloid aggregates, including nonfibrillar A oligomers and fibrillar amyloid plaques, in 5x familial AD mice following oral or intraperitoneal administration. Preliminary

2 is well tolerated and has excellentbrain barrier permeability and oral availability. Recently, we have demonstrated that mitochondrial

dynamics, morphology and function are altered in three transgenic mouse models of familial AD (APP, PS1 oligomers were the toxic species

involved in the alteration of mitochondrial dynamics early in disease progression prior to the onset ofher administration of CP2 delays the

onset and slows the progression of AD in transgenic mice, and improves mitochondrial function. Our dataterm CP2 treatment (up to 12 months) (1) does not alter the development; (2) does not

side effects; (3) does not affect animal ability to breed; (4) CP2 treatment restores Mitotrafficking in neurons from embryonic AD mice whose parents were treated with CP2; (5) CP2

ed to the untreated littermates. Thus,application of TP compounds represents a promissing therapeutic approach in the treatment of AD.


therapeutic approaches, and identification of specific biomarkers useful for early diagnosis andrd, Dr. Trushina is a recipient

(TP), exhibit anti-amyloid properties. Inparticular, TP compounds prevent cell death in celular models of Alzheimer’s Disease (AD) by reducingintracellular accumulation of toxic Aβ oligomers. The lead TP compound, code named CP2, has been

oligomers and fibrillar amyloid plaques, in 5x familial AD mice following oral or intraperitoneal administration. Preliminary





side effects; (3) does not affect animal ability to breed; (4) CP2 treatment restores Mitotrafficking in neurons from embryonic AD mice whose parents were treated with CP2; (5) CP2


37

Dr. Trushina is an Assistant Professor in the Department of Neurology at the Mayo ClinicRochester. She received her doctoral degree from Saratov State University in Russia. Dr.Trushina received her postdoctoral training at the Mayo Clinic, Rochester where sheworked with Drs. C. McMurray, R. Pagano and M. McNiven. Dr. Trushina’s laboratory isfocused on the understanding the role that mitochondrial dysfunction plays in multipleneurodegenerative disorders including Huntington’s and Alzheimer’s Diseases. Herresearch interests involve identification of the molecular mechanisms involved in theinhibition of mitochondrial dynamics and function, testing new mitochondria-targeted

therapeutic approaches, and identification of specific biomarkers useful for early diagnosis andrd, Dr. Trushina is a recipient

amyloid properties. Inparticular, TP compounds prevent cell death in celular models of Alzheimer’s Disease (AD) by reducingintracellular accumulation of toxic Aβ oligomers. The lead TP compound, code named CP2, has been






side effects; (3) does not affect animal ability to breed; (4) CP2 treatment restores Mitotrafficking in neurons from embryonic AD mice whose parents were treated with CP2; (5) CP2-treated AD


amyloid properties. Inparticular, TP compounds prevent cell death in celular models of Alzheimer’s Disease (AD) by reducingintracellular accumulation of toxic Aβ oligomers. The lead TP compound, code named CP2, has been






side effects; (3) does not affect animal ability to breed; (4) CP2 treatment restores Mitotreated AD

ed to the untreated littermates. Thus,

38

Grace

pathogenesis, and uncovering novel therapeutic strategies to prevent disease progression. Her primarytechniques include live cell imaging, elecwith particular expertise in 2preparations. Grace is a member of the Society for Neuroscience, The New York Academy of Sciencesand the Society of General Physiologists.

Targeting Neuronal Calcium Signaling to Halt AD

Grace

Rosalind Franklin University School of Medicine

Neuronal calcium signaling is fundamentallong term plasticity, and vesicle release. Because of this, neurons dedicate substantial metabolicresources to maintain calcium homeostasis and protect network stability. In neurodegeneratiinvolving calcium disruptions, such as Alzheimer’s disease (AD), alterations in calcium homeostasis havedirect effects on synaptic transmission and plasticity expression, and by association, longencoding. In AD, proximal pathogenireceptor (RyR) and IP3R channels, and we have previously shown increased RyRresponses in dendrites and spines of AD mice at young ages. The downstream implications are wideranging, but within synaptic compartments, the RyRmembrane excitability, synaptic transmission and synaptic plasticity thresholds.

Here we present the functional implications of early calcium signaling abtransmission and plasticity in AD mouse models, and offer novel pharmacological approaches to preservefunctional synaptic properties in AD mice prior to the late disease stages associated with synaptic andmemory loss. Using 2recordings in hippocampal brain slice preparations from 6demonstrate sensitized RyRhippocampal neurons. Presynaptically, disrupted ER calcium alters neurotransmitter release propertiesand depletes vesicular stores, while postsynaptically, aberrant RyRcalciumrevealed notable differences in synaptic plasticity between NonTg and AD mice as well. Acute RyRantagonism blocked LTP and LTD in NonTg mice, however, this same treatment converted LTP to milLTD, and markedly enhanced LTD, in 3xTglittle effect in NonTg mice, yet, this same treatment normalized calcium signaling in the AD mice back towithin control conditions. This includes reversisynaptic transmission, and impaired plasticity expression in AD mice back to patterns observed in NonTgmice. Therefore, this RyRprocess offers an optimistic therapeutic approach to preserving synapti

Grace E. Stutzmann



Grace E. Stutzmann



Here we present the functional implications of early calcium signaling abtransmission and plasticity in AD mouse models, and offer novel pharmacological approaches to preservefunctional synaptic properties in AD mice prior to the late disease stages associated with synaptic andmemory loss. Using 2recordings in hippocampal brain slice preparations from 6demonstrate sensitized RyRhippocampal neurons. Presynaptically, disrupted ER calcium alters neurotransmitter release propertiesand depletes vesicular stores, while postsynaptically, aberrant RyRcalcium-dependent plasma membrane channerevealed notable differences in synaptic plasticity between NonTg and AD mice as well. Acute RyRantagonism blocked LTP and LTD in NonTg mice, however, this same treatment converted LTP to milLTD, and markedly enhanced LTD, in 3xTglittle effect in NonTg mice, yet, this same treatment normalized calcium signaling in the AD mice back towithin control conditions. This includes reversisynaptic transmission, and impaired plasticity expression in AD mice back to patterns observed in NonTgmice. Therefore, this RyRprocess offers an optimistic therapeutic approach to preserving synapti

Stutzmann

Grace E.University in 1999, working with Joseph E. LeDoux. Following this, she was apostdoctoral research fellow with George Aghajanian at Yale University Medical School.A second post doctoral research fellow posParker and Frank LaFerla in the Department of Neurobiology and Behavior and theInstitute for Brain Aging and Dementia. Currently, she is an Assistant Professor inNeuroscience at Rosalind Franklin Universityresearch focuses on studying early pathogenic mechanisms contributing to AD



Stutzmann



Here we present the functional implications of early calcium signaling abtransmission and plasticity in AD mouse models, and offer novel pharmacological approaches to preservefunctional synaptic properties in AD mice prior to the late disease stages associated with synaptic andmemory loss. Using 2recordings in hippocampal brain slice preparations from 6demonstrate sensitized RyRhippocampal neurons. Presynaptically, disrupted ER calcium alters neurotransmitter release propertiesand depletes vesicular stores, while postsynaptically, aberrant RyR

dependent plasma membrane channerevealed notable differences in synaptic plasticity between NonTg and AD mice as well. Acute RyRantagonism blocked LTP and LTD in NonTg mice, however, this same treatment converted LTP to milLTD, and markedly enhanced LTD, in 3xTglittle effect in NonTg mice, yet, this same treatment normalized calcium signaling in the AD mice back towithin control conditions. This includes reversisynaptic transmission, and impaired plasticity expression in AD mice back to patterns observed in NonTgmice. Therefore, this RyRprocess offers an optimistic therapeutic approach to preserving synapti

Stutzmann, PhD, Rosalind Franklin University School of Medicine

E. Stutzmann received herUniversity in 1999, working with Joseph E. LeDoux. Following this, she was apostdoctoral research fellow with George Aghajanian at Yale University Medical School.A second post doctoral research fellow posParker and Frank LaFerla in the Department of Neurobiology and Behavior and theInstitute for Brain Aging and Dementia. Currently, she is an Assistant Professor inNeuroscience at Rosalind Franklin Universityresearch focuses on studying early pathogenic mechanisms contributing to AD

pathogenesis, and uncovering novel therapeutic strategies to prevent disease progression. Her primarytechniques include live cell imaging, elecwith particular expertise in 2-photon calcium imaging and patch clamp recordings in brain slicepreparations. Grace is a member of the Society for Neuroscience, The New York Academy of Sciencesand the Society of General Physiologists.




Here we present the functional implications of early calcium signaling abtransmission and plasticity in AD mouse models, and offer novel pharmacological approaches to preservefunctional synaptic properties in AD mice prior to the late disease stages associated with synaptic andmemory loss. Using 2-photon calcium imaging, patch clamp electrophysiology, and field potentialrecordings in hippocampal brain slice preparations from 6demonstrate sensitized RyR-evoked calcium responses in prehippocampal neurons. Presynaptically, disrupted ER calcium alters neurotransmitter release propertiesand depletes vesicular stores, while postsynaptically, aberrant RyR

dependent plasma membrane channerevealed notable differences in synaptic plasticity between NonTg and AD mice as well. Acute RyRantagonism blocked LTP and LTD in NonTg mice, however, this same treatment converted LTP to milLTD, and markedly enhanced LTD, in 3xTglittle effect in NonTg mice, yet, this same treatment normalized calcium signaling in the AD mice back towithin control conditions. This includes reversisynaptic transmission, and impaired plasticity expression in AD mice back to patterns observed in NonTgmice. Therefore, this RyR-targeted approach to normalizing aberrant calcium signaling early in the dprocess offers an optimistic therapeutic approach to preserving synapti


Stutzmann received herUniversity in 1999, working with Joseph E. LeDoux. Following this, she was apostdoctoral research fellow with George Aghajanian at Yale University Medical School.A second post doctoral research fellow posParker and Frank LaFerla in the Department of Neurobiology and Behavior and theInstitute for Brain Aging and Dementia. Currently, she is an Assistant Professor inNeuroscience at Rosalind Franklin Universityresearch focuses on studying early pathogenic mechanisms contributing to AD

pathogenesis, and uncovering novel therapeutic strategies to prevent disease progression. Her primarytechniques include live cell imaging, electrophysiology, and molecular approaches in mouse models of AD,

photon calcium imaging and patch clamp recordings in brain slicepreparations. Grace is a member of the Society for Neuroscience, The New York Academy of Sciencesand the Society of General Physiologists.


Rosalind Franklin University School of Medicine, North Chicago, IL

Neuronal calcium signaling is fundamental to a myriad of synaptic processes, including neurotransmission,long term plasticity, and vesicle release. Because of this, neurons dedicate substantial metabolicresources to maintain calcium homeostasis and protect network stability. In neurodegeneratiinvolving calcium disruptions, such as Alzheimer’s disease (AD), alterations in calcium homeostasis havedirect effects on synaptic transmission and plasticity expression, and by association, longencoding. In AD, proximal pathogenic alterations involve dysregulated ER calcium release via ryanodinereceptor (RyR) and IP3R channels, and we have previously shown increased RyRresponses in dendrites and spines of AD mice at young ages. The downstream implications are wideranging, but within synaptic compartments, the RyRmembrane excitability, synaptic transmission and synaptic plasticity thresholds.

Here we present the functional implications of early calcium signaling abtransmission and plasticity in AD mouse models, and offer novel pharmacological approaches to preservefunctional synaptic properties in AD mice prior to the late disease stages associated with synaptic and

oton calcium imaging, patch clamp electrophysiology, and field potentialrecordings in hippocampal brain slice preparations from 6

evoked calcium responses in prehippocampal neurons. Presynaptically, disrupted ER calcium alters neurotransmitter release propertiesand depletes vesicular stores, while postsynaptically, aberrant RyR

dependent plasma membrane channels to alter membrane excitability. Manipulating RyR functionrevealed notable differences in synaptic plasticity between NonTg and AD mice as well. Acute RyRantagonism blocked LTP and LTD in NonTg mice, however, this same treatment converted LTP to milLTD, and markedly enhanced LTD, in 3xTg-AD mice. Notably, chronic treatment with RyR blockers hadlittle effect in NonTg mice, yet, this same treatment normalized calcium signaling in the AD mice back towithin control conditions. This includes reversisynaptic transmission, and impaired plasticity expression in AD mice back to patterns observed in NonTg

targeted approach to normalizing aberrant calcium signaling early in the dprocess offers an optimistic therapeutic approach to preserving synapti


Stutzmann received her PhD from the Center for Neural Science at New YorkUniversity in 1999, working with Joseph E. LeDoux. Following this, she was apostdoctoral research fellow with George Aghajanian at Yale University Medical School.A second post doctoral research fellow posParker and Frank LaFerla in the Department of Neurobiology and Behavior and theInstitute for Brain Aging and Dementia. Currently, she is an Assistant Professor inNeuroscience at Rosalind Franklin Universityresearch focuses on studying early pathogenic mechanisms contributing to AD

pathogenesis, and uncovering novel therapeutic strategies to prevent disease progression. Her primarytrophysiology, and molecular approaches in mouse models of AD,

photon calcium imaging and patch clamp recordings in brain slicepreparations. Grace is a member of the Society for Neuroscience, The New York Academy of Sciences

Targeting Neuronal Calcium Signaling to Halt AD-linked Synaptic Dysfunction

, North Chicago, IL

to a myriad of synaptic processes, including neurotransmission,long term plasticity, and vesicle release. Because of this, neurons dedicate substantial metabolicresources to maintain calcium homeostasis and protect network stability. In neurodegeneratiinvolving calcium disruptions, such as Alzheimer’s disease (AD), alterations in calcium homeostasis havedirect effects on synaptic transmission and plasticity expression, and by association, long

c alterations involve dysregulated ER calcium release via ryanodinereceptor (RyR) and IP3R channels, and we have previously shown increased RyRresponses in dendrites and spines of AD mice at young ages. The downstream implications are wideranging, but within synaptic compartments, the RyR-mediated calcium alterations introduce shifts inmembrane excitability, synaptic transmission and synaptic plasticity thresholds.


oton calcium imaging, patch clamp electrophysiology, and field potentialrecordings in hippocampal brain slice preparations from 6

evoked calcium responses in prehippocampal neurons. Presynaptically, disrupted ER calcium alters neurotransmitter release propertiesand depletes vesicular stores, while postsynaptically, aberrant RyR

ls to alter membrane excitability. Manipulating RyR functionrevealed notable differences in synaptic plasticity between NonTg and AD mice as well. Acute RyRantagonism blocked LTP and LTD in NonTg mice, however, this same treatment converted LTP to mil

AD mice. Notably, chronic treatment with RyR blockers hadlittle effect in NonTg mice, yet, this same treatment normalized calcium signaling in the AD mice back towithin control conditions. This includes reversing the aberrant ER calcium responses, altered basalsynaptic transmission, and impaired plasticity expression in AD mice back to patterns observed in NonTg

targeted approach to normalizing aberrant calcium signaling early in the dprocess offers an optimistic therapeutic approach to preserving synapti


from the Center for Neural Science at New YorkUniversity in 1999, working with Joseph E. LeDoux. Following this, she was apostdoctoral research fellow with George Aghajanian at Yale University Medical School.A second post doctoral research fellow position followed at UC Irvine, working with IanParker and Frank LaFerla in the Department of Neurobiology and Behavior and theInstitute for Brain Aging and Dementia. Currently, she is an Assistant Professor inNeuroscience at Rosalind Franklin University / The Chicago Medical School. Herresearch focuses on studying early pathogenic mechanisms contributing to AD



linked Synaptic Dysfunction

, North Chicago, IL


c alterations involve dysregulated ER calcium release via ryanodinereceptor (RyR) and IP3R channels, and we have previously shown increased RyRresponses in dendrites and spines of AD mice at young ages. The downstream implications are wide

mediated calcium alterations introduce shifts inmembrane excitability, synaptic transmission and synaptic plasticity thresholds.


oton calcium imaging, patch clamp electrophysiology, and field potentialrecordings in hippocampal brain slice preparations from 6-12 week old AD and NonTg mice, we

evoked calcium responses in pre- and posthippocampal neurons. Presynaptically, disrupted ER calcium alters neurotransmitter release propertiesand depletes vesicular stores, while postsynaptically, aberrant RyR-evoked calcium release interacts with

ls to alter membrane excitability. Manipulating RyR functionrevealed notable differences in synaptic plasticity between NonTg and AD mice as well. Acute RyRantagonism blocked LTP and LTD in NonTg mice, however, this same treatment converted LTP to mil

AD mice. Notably, chronic treatment with RyR blockers hadlittle effect in NonTg mice, yet, this same treatment normalized calcium signaling in the AD mice back to

ng the aberrant ER calcium responses, altered basalsynaptic transmission, and impaired plasticity expression in AD mice back to patterns observed in NonTg

targeted approach to normalizing aberrant calcium signaling early in the dprocess offers an optimistic therapeutic approach to preserving synaptic and cognitive function in AD.


from the Center for Neural Science at New YorkUniversity in 1999, working with Joseph E. LeDoux. Following this, she was apostdoctoral research fellow with George Aghajanian at Yale University Medical School.

ition followed at UC Irvine, working with IanParker and Frank LaFerla in the Department of Neurobiology and Behavior and theInstitute for Brain Aging and Dementia. Currently, she is an Assistant Professor in

/ The Chicago Medical School. Herresearch focuses on studying early pathogenic mechanisms contributing to AD



linked Synaptic Dysfunction


c alterations involve dysregulated ER calcium release via ryanodinereceptor (RyR) and IP3R channels, and we have previously shown increased RyRresponses in dendrites and spines of AD mice at young ages. The downstream implications are wide

mediated calcium alterations introduce shifts inmembrane excitability, synaptic transmission and synaptic plasticity thresholds.

Here we present the functional implications of early calcium signaling abnormalities for synaptictransmission and plasticity in AD mouse models, and offer novel pharmacological approaches to preservefunctional synaptic properties in AD mice prior to the late disease stages associated with synaptic and

oton calcium imaging, patch clamp electrophysiology, and field potential12 week old AD and NonTg mice, we

and post-synaptic compartmentshippocampal neurons. Presynaptically, disrupted ER calcium alters neurotransmitter release properties

evoked calcium release interacts withls to alter membrane excitability. Manipulating RyR function

revealed notable differences in synaptic plasticity between NonTg and AD mice as well. Acute RyRantagonism blocked LTP and LTD in NonTg mice, however, this same treatment converted LTP to mil



targeted approach to normalizing aberrant calcium signaling early in the dc and cognitive function in AD.







to a myriad of synaptic processes, including neurotransmission,long term plasticity, and vesicle release. Because of this, neurons dedicate substantial metabolicresources to maintain calcium homeostasis and protect network stability. In neurodegenerative diseasesinvolving calcium disruptions, such as Alzheimer’s disease (AD), alterations in calcium homeostasis havedirect effects on synaptic transmission and plasticity expression, and by association, long-term memory

c alterations involve dysregulated ER calcium release via ryanodinereceptor (RyR) and IP3R channels, and we have previously shown increased RyR-evoked calciumresponses in dendrites and spines of AD mice at young ages. The downstream implications are wide

mediated calcium alterations introduce shifts in

normalities for synaptictransmission and plasticity in AD mouse models, and offer novel pharmacological approaches to preservefunctional synaptic properties in AD mice prior to the late disease stages associated with synaptic and


synaptic compartmentshippocampal neurons. Presynaptically, disrupted ER calcium alters neurotransmitter release properties


revealed notable differences in synaptic plasticity between NonTg and AD mice as well. Acute RyRantagonism blocked LTP and LTD in NonTg mice, however, this same treatment converted LTP to mil



targeted approach to normalizing aberrant calcium signaling early in the dc and cognitive function in AD.






photon calcium imaging and patch clamp recordings in brain slicepreparations. Grace is a member of the Society for Neuroscience, The New York Academy of Sciences,

to a myriad of synaptic processes, including neurotransmission,long term plasticity, and vesicle release. Because of this, neurons dedicate substantial metabolic

ve diseasesinvolving calcium disruptions, such as Alzheimer’s disease (AD), alterations in calcium homeostasis have

term memoryc alterations involve dysregulated ER calcium release via ryanodine

evoked calciumresponses in dendrites and spines of AD mice at young ages. The downstream implications are wide-




synaptic compartments of ADhippocampal neurons. Presynaptically, disrupted ER calcium alters neurotransmitter release properties


revealed notable differences in synaptic plasticity between NonTg and AD mice as well. Acute RyRantagonism blocked LTP and LTD in NonTg mice, however, this same treatment converted LTP to mild



targeted approach to normalizing aberrant calcium signaling early in the diseasec and cognitive function in AD.

postdoctoral research fellow with George Aghajanian at Yale University Medical School.

to a myriad of synaptic processes, including neurotransmission,long term plasticity, and vesicle release. Because of this, neurons dedicate substantial metabolic

ve diseasesinvolving calcium disruptions, such as Alzheimer’s disease (AD), alterations in calcium homeostasis have

term memoryc alterations involve dysregulated ER calcium release via ryanodine

evoked calcium




of ADhippocampal neurons. Presynaptically, disrupted ER calcium alters neurotransmitter release properties


revealed notable differences in synaptic plasticity between NonTg and AD mice as well. Acute RyRd



isease


Carmela

brain.accumulate more Abeta in their brains and at an eaage. To this endsupporting evidence that inhibiting APP dimerization with small molecule compounds could constituteanother avenue for lowering Abeta in the brain. In the normal aging projectrhesus monkey as a model for understanding changes that occur in the white matter during nonpathological aging. With microarray analysisdysfunction leading to cognitive decline. An example is Klotho, a cytoprotective, antiAbrahammice.aging and disease.oligodendrocyte precursor cells into mature, myelinawhite matter and AD is compromised, enhancing Klotho expression could be beneficial by inducing myelinrepair in normal aging and AD.

Klotho Enhances Oligodendrocyte Maturation and Myelination

Carmela

Boston University School of Medicine

White matter and myelin abnormalities occur during normal aging, in Alzheimer’s disease and, to a largerextent, in Multiple Sclerosis. Although the mechanisms behind this deterioration of myeconditions may be entirely different, repair of the damaged myelin by the oligodendrocytes is universallynecessary. Here we present a connection between the antimyelin.Our group has previously showof the brain and that an agePredominantly generated in brain and kidney, Klotho overexpression extends lKlotho accelerates the development of agingunknown, loss of Klotho expression leads to cognitive deficits that are not well explained. In the presentstudy, we found signifanalysis and phosphoprotein Western analysis revealed Klotho’s downstream effects involve Akt and ERKsignal pathways. Klotho increased primary oligodendrocytes maturatifunction blocked this effect on oligodendrocytes. In vivo studies of Klotho knockout mice and their controllittermates revealed that these mice have a significant reduction in major myelin protein and geneexpression comparsignificantly lower in Klotho knockout mice. However, the most striking myelin abnormalities were observedat the ultrastructural level. Klotho knockout mice exhibited signerve and corpus callosum. In order to decipher the mechanisms by which Klotho affects oligodendrocytes,we used enrichment analysis to predict potential transcriptional factors involved in regulating Klothooligodendrocytic MO3.13 cells. These studies are expected to provide a better understanding of thefunctions of Klotho in myelin biology, and lead to ways to protect brain myelinchanges.


Carmela R.

brain. She also works onaccumulate more Abeta in their brains and at an eaage. To this endsupporting evidence that inhibiting APP dimerization with small molecule compounds could constituteanother avenue for lowering Abeta in the brain. In the normal aging projectrhesus monkey as a model for understanding changes that occur in the white matter during nonpathological aging. With microarray analysisdysfunction leading to cognitive decline. An example is Klotho, a cytoprotective, antiAbraham found that Klotho expression is considerably decreased in the aged brains of monkeys, rats,mice. She and her teamaging and disease.oligodendrocyte precursor cells into mature, myelinawhite matter and AD is compromised, enhancing Klotho expression could be beneficial by inducing myelinrepair in normal aging and AD.


Carmela R. Abraham


White matter and myelin abnormalities occur during normal aging, in Alzheimer’s disease and, to a largerextent, in Multiple Sclerosis. Although the mechanisms behind this deterioration of myeconditions may be entirely different, repair of the damaged myelin by the oligodendrocytes is universallynecessary. Here we present a connection between the antimyelin.Our group has previously showof the brain and that an agePredominantly generated in brain and kidney, Klotho overexpression extends lKlotho accelerates the development of agingunknown, loss of Klotho expression leads to cognitive deficits that are not well explained. In the presentstudy, we found signifanalysis and phosphoprotein Western analysis revealed Klotho’s downstream effects involve Akt and ERKsignal pathways. Klotho increased primary oligodendrocytes maturatifunction blocked this effect on oligodendrocytes. In vivo studies of Klotho knockout mice and their controllittermates revealed that these mice have a significant reduction in major myelin protein and geneexpression comparsignificantly lower in Klotho knockout mice. However, the most striking myelin abnormalities were observedat the ultrastructural level. Klotho knockout mice exhibited signerve and corpus callosum. In order to decipher the mechanisms by which Klotho affects oligodendrocytes,we used enrichment analysis to predict potential transcriptional factors involved in regulating Klothooligodendrocytic MO3.13 cells. These studies are expected to provide a better understanding of thefunctions of Klotho in myelin biology, and lead to ways to protect brain myelinchanges.


R. Abraham, PhD,

Dr. Abrahamshe participated in numerous studies trying to understand the biology of the amyoidprecursor protein (APP), including its processing and function, and its neurotoxic andsynaptotoxic fragment, amyloid beta protein (Abeta).Neuroscience from Harvard University and joined Boston University School of Medicine in1989 wheremolecular mechanisms leading to normal brain aging and the pathological proceculminate in AD. AD neuropathology is characterized by the accumulation of Abeta in the

She also works onaccumulate more Abeta in their brains and at an eaage. To this end she and her teamsupporting evidence that inhibiting APP dimerization with small molecule compounds could constituteanother avenue for lowering Abeta in the brain. In the normal aging projectrhesus monkey as a model for understanding changes that occur in the white matter during nonpathological aging. With microarray analysisdysfunction leading to cognitive decline. An example is Klotho, a cytoprotective, anti

found that Klotho expression is considerably decreased in the aged brains of monkeys, rats,She and her team

aging and disease. They have alsooligodendrocyte precursor cells into mature, myelinawhite matter and AD is compromised, enhancing Klotho expression could be beneficial by inducing myelinrepair in normal aging and AD.


R. Abraham


White matter and myelin abnormalities occur during normal aging, in Alzheimer’s disease and, to a largerextent, in Multiple Sclerosis. Although the mechanisms behind this deterioration of myeconditions may be entirely different, repair of the damaged myelin by the oligodendrocytes is universallynecessary. Here we present a connection between the anti

Our group has previously showof the brain and that an agePredominantly generated in brain and kidney, Klotho overexpression extends lKlotho accelerates the development of agingunknown, loss of Klotho expression leads to cognitive deficits that are not well explained. In the presentstudy, we found significant effects of Klotho on oligodendrocyte functions including myelination. Microarrayanalysis and phosphoprotein Western analysis revealed Klotho’s downstream effects involve Akt and ERKsignal pathways. Klotho increased primary oligodendrocytes maturatifunction blocked this effect on oligodendrocytes. In vivo studies of Klotho knockout mice and their controllittermates revealed that these mice have a significant reduction in major myelin protein and geneexpression compared to control mice. By immunohistochemistry the total number of oligodendrocytes wassignificantly lower in Klotho knockout mice. However, the most striking myelin abnormalities were observedat the ultrastructural level. Klotho knockout mice exhibited signerve and corpus callosum. In order to decipher the mechanisms by which Klotho affects oligodendrocytes,we used enrichment analysis to predict potential transcriptional factors involved in regulating Klothooligodendrocytic MO3.13 cells. These studies are expected to provide a better understanding of thefunctions of Klotho in myelin biology, and lead to ways to protect brain myelin


Abraham, PhD,

Dr. Abraham was first introduced to Alzheimer’s disease (ADparticipated in numerous studies trying to understand the biology of the amyoid

precursor protein (APP), including its processing and function, and its neurotoxic andsynaptotoxic fragment, amyloid beta protein (Abeta).Neuroscience from Harvard University and joined Boston University School of Medicine in1989 where she became a Professor in 1999.molecular mechanisms leading to normal brain aging and the pathological proceculminate in AD. AD neuropathology is characterized by the accumulation of Abeta in the

She also works on understandingaccumulate more Abeta in their brains and at an ea

she and her teamsupporting evidence that inhibiting APP dimerization with small molecule compounds could constituteanother avenue for lowering Abeta in the brain. In the normal aging projectrhesus monkey as a model for understanding changes that occur in the white matter during nonpathological aging. With microarray analysisdysfunction leading to cognitive decline. An example is Klotho, a cytoprotective, anti

found that Klotho expression is considerably decreased in the aged brains of monkeys, rats,She and her team are now working to comprehensively characterize the role of Klotho in normal

They have alsooligodendrocyte precursor cells into mature, myelinawhite matter and AD is compromised, enhancing Klotho expression could be beneficial by inducing myelinrepair in normal aging and AD.




Our group has previously shown that myelin abnormalities and loss characterize the normal aging processof the brain and that an age-associated reduction in Klotho is conserved across a wide range of species.Predominantly generated in brain and kidney, Klotho overexpression extends lKlotho accelerates the development of agingunknown, loss of Klotho expression leads to cognitive deficits that are not well explained. In the present

icant effects of Klotho on oligodendrocyte functions including myelination. Microarrayanalysis and phosphoprotein Western analysis revealed Klotho’s downstream effects involve Akt and ERKsignal pathways. Klotho increased primary oligodendrocytes maturatifunction blocked this effect on oligodendrocytes. In vivo studies of Klotho knockout mice and their controllittermates revealed that these mice have a significant reduction in major myelin protein and gene

ed to control mice. By immunohistochemistry the total number of oligodendrocytes wassignificantly lower in Klotho knockout mice. However, the most striking myelin abnormalities were observedat the ultrastructural level. Klotho knockout mice exhibited signerve and corpus callosum. In order to decipher the mechanisms by which Klotho affects oligodendrocytes,we used enrichment analysis to predict potential transcriptional factors involved in regulating Klothooligodendrocytic MO3.13 cells. These studies are expected to provide a better understanding of thefunctions of Klotho in myelin biology, and lead to ways to protect brain myelin

Abraham, PhD, Boston University School of Medicine

was first introduced to Alzheimer’s disease (ADparticipated in numerous studies trying to understand the biology of the amyoid

precursor protein (APP), including its processing and function, and its neurotoxic andsynaptotoxic fragment, amyloid beta protein (Abeta).Neuroscience from Harvard University and joined Boston University School of Medicine in

became a Professor in 1999.molecular mechanisms leading to normal brain aging and the pathological proceculminate in AD. AD neuropathology is characterized by the accumulation of Abeta in the

ing the reason patients carrying mutations that result in early onset ADaccumulate more Abeta in their brains and at an ea

she and her team study the role of APP dimerization in Abeta formation.supporting evidence that inhibiting APP dimerization with small molecule compounds could constituteanother avenue for lowering Abeta in the brain. In the normal aging projectrhesus monkey as a model for understanding changes that occur in the white matter during nonpathological aging. With microarray analysis they haddysfunction leading to cognitive decline. An example is Klotho, a cytoprotective, anti

found that Klotho expression is considerably decreased in the aged brains of monkeys, rats,are now working to comprehensively characterize the role of Klotho in normal

They have also discovered recently that Klotho can induce the differentiation ofoligodendrocyte precursor cells into mature, myelinawhite matter and AD is compromised, enhancing Klotho expression could be beneficial by inducing myelin


Boston University School of Medicine, Boston, MA


n that myelin abnormalities and loss characterize the normal aging processassociated reduction in Klotho is conserved across a wide range of species.

Predominantly generated in brain and kidney, Klotho overexpression extends lKlotho accelerates the development of aging-like phenotypes. While the function of Klotho in brain isunknown, loss of Klotho expression leads to cognitive deficits that are not well explained. In the present

icant effects of Klotho on oligodendrocyte functions including myelination. Microarrayanalysis and phosphoprotein Western analysis revealed Klotho’s downstream effects involve Akt and ERKsignal pathways. Klotho increased primary oligodendrocytes maturatifunction blocked this effect on oligodendrocytes. In vivo studies of Klotho knockout mice and their controllittermates revealed that these mice have a significant reduction in major myelin protein and gene




precursor protein (APP), including its processing and function, and its neurotoxic andsynaptotoxic fragment, amyloid beta protein (Abeta).Neuroscience from Harvard University and joined Boston University School of Medicine in

became a Professor in 1999.molecular mechanisms leading to normal brain aging and the pathological proceculminate in AD. AD neuropathology is characterized by the accumulation of Abeta in the

the reason patients carrying mutations that result in early onset ADaccumulate more Abeta in their brains and at an earlier age that those patients who become ill at an older

study the role of APP dimerization in Abeta formation.supporting evidence that inhibiting APP dimerization with small molecule compounds could constituteanother avenue for lowering Abeta in the brain. In the normal aging projectrhesus monkey as a model for understanding changes that occur in the white matter during non

they had identified genes that play crucial roles in braindysfunction leading to cognitive decline. An example is Klotho, a cytoprotective, anti


discovered recently that Klotho can induce the differentiation ofoligodendrocyte precursor cells into mature, myelinating oligodendrocytes. Since the myelin in the agingwhite matter and AD is compromised, enhancing Klotho expression could be beneficial by inducing myelin


, Boston, MA



Predominantly generated in brain and kidney, Klotho overexpression extends llike phenotypes. While the function of Klotho in brain is

unknown, loss of Klotho expression leads to cognitive deficits that are not well explained. In the presenticant effects of Klotho on oligodendrocyte functions including myelination. Microarray

analysis and phosphoprotein Western analysis revealed Klotho’s downstream effects involve Akt and ERKsignal pathways. Klotho increased primary oligodendrocytes maturatifunction blocked this effect on oligodendrocytes. In vivo studies of Klotho knockout mice and their controllittermates revealed that these mice have a significant reduction in major myelin protein and gene




precursor protein (APP), including its processing and function, and its neurotoxic andsynaptotoxic fragment, amyloid beta protein (Abeta). Dr. AbrahamNeuroscience from Harvard University and joined Boston University School of Medicine in

became a Professor in 1999. Dr. Abraham’smolecular mechanisms leading to normal brain aging and the pathological proceculminate in AD. AD neuropathology is characterized by the accumulation of Abeta in the

the reason patients carrying mutations that result in early onset ADrlier age that those patients who become ill at an older

study the role of APP dimerization in Abeta formation.supporting evidence that inhibiting APP dimerization with small molecule compounds could constituteanother avenue for lowering Abeta in the brain. In the normal aging projectrhesus monkey as a model for understanding changes that occur in the white matter during non

identified genes that play crucial roles in braindysfunction leading to cognitive decline. An example is Klotho, a cytoprotective, anti


discovered recently that Klotho can induce the differentiation ofting oligodendrocytes. Since the myelin in the aging

white matter and AD is compromised, enhancing Klotho expression could be beneficial by inducing myelin


White matter and myelin abnormalities occur during normal aging, in Alzheimer’s disease and, to a largerextent, in Multiple Sclerosis. Although the mechanisms behind this deterioration of myeconditions may be entirely different, repair of the damaged myelin by the oligodendrocytes is universallynecessary. Here we present a connection between the anti-aging protein Klotho, oligodendrocytes and


Predominantly generated in brain and kidney, Klotho overexpression extends llike phenotypes. While the function of Klotho in brain is


analysis and phosphoprotein Western analysis revealed Klotho’s downstream effects involve Akt and ERKsignal pathways. Klotho increased primary oligodendrocytes maturatifunction blocked this effect on oligodendrocytes. In vivo studies of Klotho knockout mice and their controllittermates revealed that these mice have a significant reduction in major myelin protein and gene

ed to control mice. By immunohistochemistry the total number of oligodendrocytes wassignificantly lower in Klotho knockout mice. However, the most striking myelin abnormalities were observedat the ultrastructural level. Klotho knockout mice exhibited significantly impaired myelination of the opticnerve and corpus callosum. In order to decipher the mechanisms by which Klotho affects oligodendrocytes,we used enrichment analysis to predict potential transcriptional factors involved in regulating Klothooligodendrocytic MO3.13 cells. These studies are expected to provide a better understanding of thefunctions of Klotho in myelin biology, and lead to ways to protect brain myelin


was first introduced to Alzheimer’s disease (AD) research in 1980.participated in numerous studies trying to understand the biology of the amyoid

precursor protein (APP), including its processing and function, and its neurotoxic andDr. Abraham

Neuroscience from Harvard University and joined Boston University School of Medicine inDr. Abraham’s

molecular mechanisms leading to normal brain aging and the pathological proceculminate in AD. AD neuropathology is characterized by the accumulation of Abeta in the


study the role of APP dimerization in Abeta formation.supporting evidence that inhibiting APP dimerization with small molecule compounds could constituteanother avenue for lowering Abeta in the brain. In the normal aging project Dr. Abraham’s teamrhesus monkey as a model for understanding changes that occur in the white matter during non

identified genes that play crucial roles in braindysfunction leading to cognitive decline. An example is Klotho, a cytoprotective, anti




White matter and myelin abnormalities occur during normal aging, in Alzheimer’s disease and, to a largerextent, in Multiple Sclerosis. Although the mechanisms behind this deterioration of myeconditions may be entirely different, repair of the damaged myelin by the oligodendrocytes is universally

aging protein Klotho, oligodendrocytes and


Predominantly generated in brain and kidney, Klotho overexpression extends life span whereas loss oflike phenotypes. While the function of Klotho in brain is


analysis and phosphoprotein Western analysis revealed Klotho’s downstream effects involve Akt and ERKsignal pathways. Klotho increased primary oligodendrocytes maturation and inhibition of Akt or ERKfunction blocked this effect on oligodendrocytes. In vivo studies of Klotho knockout mice and their controllittermates revealed that these mice have a significant reduction in major myelin protein and gene

ed to control mice. By immunohistochemistry the total number of oligodendrocytes wassignificantly lower in Klotho knockout mice. However, the most striking myelin abnormalities were observed

nificantly impaired myelination of the opticnerve and corpus callosum. In order to decipher the mechanisms by which Klotho affects oligodendrocytes,we used enrichment analysis to predict potential transcriptional factors involved in regulating Klothooligodendrocytic MO3.13 cells. These studies are expected to provide a better understanding of thefunctions of Klotho in myelin biology, and lead to ways to protect brain myelin against age


) research in 1980.participated in numerous studies trying to understand the biology of the amyoid

precursor protein (APP), including its processing and function, and its neurotoxic andDr. Abraham obtained

Neuroscience from Harvard University and joined Boston University School of Medicine inlaboratory studies the

molecular mechanisms leading to normal brain aging and the pathological proceculminate in AD. AD neuropathology is characterized by the accumulation of Abeta in the


study the role of APP dimerization in Abeta formation.supporting evidence that inhibiting APP dimerization with small molecule compounds could constitute

Dr. Abraham’s teamrhesus monkey as a model for understanding changes that occur in the white matter during non

identified genes that play crucial roles in braindysfunction leading to cognitive decline. An example is Klotho, a cytoprotective, anti-aging protein.




White matter and myelin abnormalities occur during normal aging, in Alzheimer’s disease and, to a largerextent, in Multiple Sclerosis. Although the mechanisms behind this deterioration of myelin in theseconditions may be entirely different, repair of the damaged myelin by the oligodendrocytes is universally

aging protein Klotho, oligodendrocytes and


ife span whereas loss oflike phenotypes. While the function of Klotho in brain is


analysis and phosphoprotein Western analysis revealed Klotho’s downstream effects involve Akt and ERKon and inhibition of Akt or ERK

function blocked this effect on oligodendrocytes. In vivo studies of Klotho knockout mice and their controllittermates revealed that these mice have a significant reduction in major myelin protein and gene


nificantly impaired myelination of the opticnerve and corpus callosum. In order to decipher the mechanisms by which Klotho affects oligodendrocytes,we used enrichment analysis to predict potential transcriptional factors involved in regulating Klothooligodendrocytic MO3.13 cells. These studies are expected to provide a better understanding of the

against age

39

) research in 1980. Since thenparticipated in numerous studies trying to understand the biology of the amyoid

precursor protein (APP), including its processing and function, and its neurotoxic andobtained her PhD in


molecular mechanisms leading to normal brain aging and the pathological processes thatculminate in AD. AD neuropathology is characterized by the accumulation of Abeta in the


study the role of APP dimerization in Abeta formation. They havesupporting evidence that inhibiting APP dimerization with small molecule compounds could constitute

Dr. Abraham’s team utilizes therhesus monkey as a model for understanding changes that occur in the white matter during non-

identified genes that play crucial roles in brainaging protein. Dr.

found that Klotho expression is considerably decreased in the aged brains of monkeys, rats, andare now working to comprehensively characterize the role of Klotho in normal



White matter and myelin abnormalities occur during normal aging, in Alzheimer’s disease and, to a largerlin in these

conditions may be entirely different, repair of the damaged myelin by the oligodendrocytes is universallyaging protein Klotho, oligodendrocytes and







nificantly impaired myelination of the opticnerve and corpus callosum. In order to decipher the mechanisms by which Klotho affects oligodendrocytes,we used enrichment analysis to predict potential transcriptional factors involved in regulating Klotho-treatedoligodendrocytic MO3.13 cells. These studies are expected to provide a better understanding of the

against age-dependent

Since thenparticipated in numerous studies trying to understand the biology of the amyoid

precursor protein (APP), including its processing and function, and its neurotoxic andPhD in


sses thatculminate in AD. AD neuropathology is characterized by the accumulation of Abeta in the


havesupporting evidence that inhibiting APP dimerization with small molecule compounds could constitute

the

identified genes that play crucial roles in brainDr.

andare now working to comprehensively characterize the role of Klotho in normal



White matter and myelin abnormalities occur during normal aging, in Alzheimer’s disease and, to a largerlin in these

conditions may be entirely different, repair of the damaged myelin by the oligodendrocytes is universallyaging protein Klotho, oligodendrocytes and







nificantly impaired myelination of the opticnerve and corpus callosum. In order to decipher the mechanisms by which Klotho affects oligodendrocytes,

atedoligodendrocytic MO3.13 cells. These studies are expected to provide a better understanding of the

dependent

40

Pavel A. Petukhov

Research interests: Medicinal chemistry, computerDesign of potent photoreacphotocrosslink to different HDAC isoforms, and application of this knowledge to discovery of potent HDACinhibitors with a desired HDAC isoform activity and an improved ADMET profile. Discinhibitors of pantothenate synthetase and malate synthase, novel targets for nontuberculosis. Design and development of novel therapeutics for neurological diseases, cancer, tuberculosis,and hepatitis B.

Mapping the Binding Site of HDAC 2 for the Design of Novel HDAC Inhibitors Lacking Zinc BindingGroup

Pavel A. Petukhov,Richard van Breemen

University of Illinois at Chicago

Inhibition of HDAC2 is an attractive therapeutic avenue for neurodegenerative diseases associated withlearning and memory impairment. To uncover the full potential of inhibition of HDAC2 novel safe for longterm use and isoformto design HDAC2 inhibitors lacking the zinc chelating group by targeting novel adjacent to the catalytic sitepockets. In this talk we will present the first step in this directionpotent photoreactive HDAC 2 inhibitors and their use for the Binding Ensemble Profiling with PhotoaffinityLabeling (BEProFL) of HDAC2.

Pavel A. Petukhov


Mapping the Binding Site of HDAC 2 for the Design of Novel HDAC Inhibitors Lacking Zinc BindingGroup

Pavel A. Petukhov,Richard van Breemen


Inhibition of HDAC2 is an attractive therapeutic avenue for neurodegenerative diseases associated withlearning and memory impairment. To uncover the full potential of inhibition of HDAC2 novel safe for longterm use and isoformto design HDAC2 inhibitors lacking the zinc chelating group by targeting novel adjacent to the catalytic sitepockets. In this talk we will present the first step in this directionpotent photoreactive HDAC 2 inhibitors and their use for the Binding Ensemble Profiling with PhotoaffinityLabeling (BEProFL) of HDAC2.

Pavel A. Petukhov, PhD,

PhD with Dr. Alexey Tkachev at Novosibirsk Institute of Organic Chemistry (1998),postdoc with Dr. John Keana at University of Oregon (1998Kozikowski at Georgetown University (2000Illinois at Chicago, College of Pharmacy, Department of Medicinal Chemistry andPharmacognosy (2004(2008-present), Associate Faculty at Institute for Tuberculosis ResearAssociate Professor at the Bioengineering Department, University of Illinois at Chicago(2007 - present).


Mapping the Binding Site of HDAC 2 for the Design of Novel HDAC Inhibitors Lacking Zinc Binding

Pavel A. Petukhov, Aditya S. Vaidya, Emma Mendonca, Bhargava Karumudi, He Bai, Caleb K. Nienow,Richard van Breemen


Inhibition of HDAC2 is an attractive therapeutic avenue for neurodegenerative diseases associated withlearning and memory impairment. To uncover the full potential of inhibition of HDAC2 novel safe for longterm use and isoform-selective HDAto design HDAC2 inhibitors lacking the zinc chelating group by targeting novel adjacent to the catalytic sitepockets. In this talk we will present the first step in this directionpotent photoreactive HDAC 2 inhibitors and their use for the Binding Ensemble Profiling with PhotoaffinityLabeling (BEProFL) of HDAC2.

, PhD, University of

with Dr. Alexey Tkachev at Novosibirsk Institute of Organic Chemistry (1998),postdoc with Dr. John Keana at University of Oregon (1998Kozikowski at Georgetown University (2000Illinois at Chicago, College of Pharmacy, Department of Medicinal Chemistry andPharmacognosy (2004

present), Associate Faculty at Institute for Tuberculosis ResearAssociate Professor at the Bioengineering Department, University of Illinois at Chicago

present).Research interests: Medicinal chemistry, computerDesign of potent photoreactive probes for histone deacetylases (HDAC), understanding how theyphotocrosslink to different HDAC isoforms, and application of this knowledge to discovery of potent HDACinhibitors with a desired HDAC isoform activity and an improved ADMET profile. Discinhibitors of pantothenate synthetase and malate synthase, novel targets for nontuberculosis. Design and development of novel therapeutics for neurological diseases, cancer, tuberculosis,


Aditya S. Vaidya, Emma Mendonca, Bhargava Karumudi, He Bai, Caleb K. Nienow,

University of Illinois at Chicago, Chicago, IL

Inhibition of HDAC2 is an attractive therapeutic avenue for neurodegenerative diseases associated withlearning and memory impairment. To uncover the full potential of inhibition of HDAC2 novel safe for long

selective HDAC 2 inhibitors are needed. We hypothesized that it would be possibleto design HDAC2 inhibitors lacking the zinc chelating group by targeting novel adjacent to the catalytic sitepockets. In this talk we will present the first step in this directionpotent photoreactive HDAC 2 inhibitors and their use for the Binding Ensemble Profiling with PhotoaffinityLabeling (BEProFL) of HDAC2.

University of

with Dr. Alexey Tkachev at Novosibirsk Institute of Organic Chemistry (1998),postdoc with Dr. John Keana at University of Oregon (1998Kozikowski at Georgetown University (2000Illinois at Chicago, College of Pharmacy, Department of Medicinal Chemistry andPharmacognosy (2004-2008), Associate Professor at University of Illinois at Chicago

present), Associate Faculty at Institute for Tuberculosis ResearAssociate Professor at the Bioengineering Department, University of Illinois at Chicago

Research interests: Medicinal chemistry, computertive probes for histone deacetylases (HDAC), understanding how they

photocrosslink to different HDAC isoforms, and application of this knowledge to discovery of potent HDACinhibitors with a desired HDAC isoform activity and an improved ADMET profile. Discinhibitors of pantothenate synthetase and malate synthase, novel targets for nontuberculosis. Design and development of novel therapeutics for neurological diseases, cancer, tuberculosis,



Chicago, IL


C 2 inhibitors are needed. We hypothesized that it would be possibleto design HDAC2 inhibitors lacking the zinc chelating group by targeting novel adjacent to the catalytic sitepockets. In this talk we will present the first step in this directionpotent photoreactive HDAC 2 inhibitors and their use for the Binding Ensemble Profiling with Photoaffinity


with Dr. Alexey Tkachev at Novosibirsk Institute of Organic Chemistry (1998),postdoc with Dr. John Keana at University of Oregon (1998Kozikowski at Georgetown University (2000Illinois at Chicago, College of Pharmacy, Department of Medicinal Chemistry and

2008), Associate Professor at University of Illinois at Chicagopresent), Associate Faculty at Institute for Tuberculosis Resear

Associate Professor at the Bioengineering Department, University of Illinois at Chicago

Research interests: Medicinal chemistry, computer-aided drug design, chemical biology, drug discovery.tive probes for histone deacetylases (HDAC), understanding how they





C 2 inhibitors are needed. We hypothesized that it would be possibleto design HDAC2 inhibitors lacking the zinc chelating group by targeting novel adjacent to the catalytic sitepockets. In this talk we will present the first step in this directionpotent photoreactive HDAC 2 inhibitors and their use for the Binding Ensemble Profiling with Photoaffinity

Illinois at Chicago

with Dr. Alexey Tkachev at Novosibirsk Institute of Organic Chemistry (1998),postdoc with Dr. John Keana at University of Oregon (1998Kozikowski at Georgetown University (2000-2003), Assistant ProfeIllinois at Chicago, College of Pharmacy, Department of Medicinal Chemistry and



aided drug design, chemical biology, drug discovery.tive probes for histone deacetylases (HDAC), understanding how they





C 2 inhibitors are needed. We hypothesized that it would be possibleto design HDAC2 inhibitors lacking the zinc chelating group by targeting novel adjacent to the catalytic sitepockets. In this talk we will present the first step in this direction – desipotent photoreactive HDAC 2 inhibitors and their use for the Binding Ensemble Profiling with Photoaffinity

Illinois at Chicago

with Dr. Alexey Tkachev at Novosibirsk Institute of Organic Chemistry (1998),postdoc with Dr. John Keana at University of Oregon (1998-2000), postdoc with Dr. Alan

2003), Assistant ProfeIllinois at Chicago, College of Pharmacy, Department of Medicinal Chemistry and








C 2 inhibitors are needed. We hypothesized that it would be possibleto design HDAC2 inhibitors lacking the zinc chelating group by targeting novel adjacent to the catalytic site

design and synthesis of a series ofpotent photoreactive HDAC 2 inhibitors and their use for the Binding Ensemble Profiling with Photoaffinity

with Dr. Alexey Tkachev at Novosibirsk Institute of Organic Chemistry (1998),2000), postdoc with Dr. Alan

2003), Assistant Professor at University ofIllinois at Chicago, College of Pharmacy, Department of Medicinal Chemistry and

2008), Associate Professor at University of Illinois at Chicagopresent), Associate Faculty at Institute for Tuberculosis Research (2004



photocrosslink to different HDAC isoforms, and application of this knowledge to discovery of potent HDACinhibitors with a desired HDAC isoform activity and an improved ADMET profile. Discovery of novel potentinhibitors of pantothenate synthetase and malate synthase, novel targets for non-replicating persistenttuberculosis. Design and development of novel therapeutics for neurological diseases, cancer, tuberculosis,





gn and synthesis of a series ofpotent photoreactive HDAC 2 inhibitors and their use for the Binding Ensemble Profiling with Photoaffinity


ssor at University ofIllinois at Chicago, College of Pharmacy, Department of Medicinal Chemistry and

2008), Associate Professor at University of Illinois at Chicagoch (2004 – present),



photocrosslink to different HDAC isoforms, and application of this knowledge to discovery of potent HDACovery of novel potentreplicating persistent

tuberculosis. Design and development of novel therapeutics for neurological diseases, cancer, tuberculosis,



Inhibition of HDAC2 is an attractive therapeutic avenue for neurodegenerative diseases associated withlearning and memory impairment. To uncover the full potential of inhibition of HDAC2 novel safe for long-




ssor at University ofIllinois at Chicago, College of Pharmacy, Department of Medicinal Chemistry and

2008), Associate Professor at University of Illinois at Chicagopresent),



photocrosslink to different HDAC isoforms, and application of this knowledge to discovery of potent HDACovery of novel potentreplicating persistent

tuberculosis. Design and development of novel therapeutics for neurological diseases, cancer, tuberculosis,


Inhibition of HDAC2 is an attractive therapeutic avenue for neurodegenerative diseases associated with




Karl

(NWFZ) of the Charité, Berlin and later became Assistant and Adjunct ProfeJohannes MüllerSouthern Research in 2006, where he is currently an independent PI in the Biochemistry and MolecularBiology DepartmentComprehensive Neuroscience Center (CNC) at The University of Alabama at Birmingham(UAB).Throughout his research career, Dr. Braunewell has focused on molecular and cellular mechanisunderlying brain function, particularly learning and memory. His current interest focuses on the role ofneuronal calcium sensors and nicotinic acetylcholine receptors in addiction, schizophrenia and Alzheimer’sdisease. At Southern Research, Dr. BrauneCNS disorders including Alzheimer's disease, addiction, depression and schizophrenia.

Targeting the Neuronal Calcium Sensor (NCS) Protein, VILIPDisord

Karl

Southern Research Institute

VILIPbinding proteins, and has been implicated in Alzheimer’s disease (AD). Lower expression of VILIPprotein and mRNA were found in hippocampus, amygdala, cingreduced expression levels correlate with neurofibrillar tangle content and the MMSE (mini mental statusexamination) score. Increased cerebrospinal fluid content of VILIPdiseasoffer diagnostic utility for early AD, and can predict future cognitive impairment in cognitively normalindividuals similarly to tau/Aβ42. Several lines of experexpression of VILIPpathways implicated in synaptic plasticity and memory, and one of its targets, theacetylchocognitive decline in AD. We have used the available knowledge on VILIPassays for chemical compounds modulating functional activity ofdevelop activators of VILIPVILIPpotentageing population.


Karl-Heinz Braunewell

(NWFZ) of the Charité, Berlin and later became Assistant and Adjunct ProfeJohannes MüllerSouthern Research in 2006, where he is currently an independent PI in the Biochemistry and MolecularBiology DepartmentComprehensive Neuroscience Center (CNC) at The University of Alabama at Birmingham(UAB).Throughout his research career, Dr. Braunewell has focused on molecular and cellular mechanisunderlying brain function, particularly learning and memory. His current interest focuses on the role ofneuronal calcium sensors and nicotinic acetylcholine receptors in addiction, schizophrenia and Alzheimer’sdisease. At Southern Research, Dr. BrauneCNS disorders including Alzheimer's disease, addiction, depression and schizophrenia.

Targeting the Neuronal Calcium Sensor (NCS) Protein, VILIPDisorders

Karl-Heinz Braunewell


VILIP-1 (visininbinding proteins, and has been implicated in Alzheimer’s disease (AD). Lower expression of VILIPprotein and mRNA were found in hippocampus, amygdala, cingreduced expression levels correlate with neurofibrillar tangle content and the MMSE (mini mental statusexamination) score. Increased cerebrospinal fluid content of VILIPdisease biomarker for AD. The most recent study in 2011 concluded that CSF VILIPoffer diagnostic utility for early AD, and can predict future cognitive impairment in cognitively normalindividuals similarly to tau/Aβ42. Several lines of experexpression of VILIPpathways implicated in synaptic plasticity and memory, and one of its targets, theacetylcholine receptor, has been frequently linked to learning and memory processes as well as tocognitive decline in AD. We have used the available knowledge on VILIPassays for chemical compounds modulating functional activity ofdevelop activators of VILIPVILIP-1 likely plays a role in disease mechanisms of cognitive deficits, and therefore, comprises a novelpotential drug target for treatment of such cognitive impairments in neurodegnerative disorders and in theageing population.


Heinz Braunewell

Dr. Braunewell obtained hisM. Schachner) at the Federal Institute of Technology in Zurich, Switzerland, and receivedfurther postdoctoral research training at the Department for NeurochemistrBiology (Prof. E.D. Gundelfinger), LeibnizGermany. In 1998, Dr. Braunewell became head of the Signal Transduction ResearchGroup at the LeibnizMedical Faculty of the Ottoheaded the Signal Transduction Research Group at the Neuroscience Research Center

(NWFZ) of the Charité, Berlin and later became Assistant and Adjunct ProfeJohannes Müller-Institute, Medical Faculty, Charité, at Humboldt University in Berlin. Dr. Braunewell joinedSouthern Research in 2006, where he is currently an independent PI in the Biochemistry and MolecularBiology Department of the Drug Discovery Division. He is also a member of the faculty at theComprehensive Neuroscience Center (CNC) at The University of Alabama at Birmingham(UAB).Throughout his research career, Dr. Braunewell has focused on molecular and cellular mechanisunderlying brain function, particularly learning and memory. His current interest focuses on the role ofneuronal calcium sensors and nicotinic acetylcholine receptors in addiction, schizophrenia and Alzheimer’sdisease. At Southern Research, Dr. BrauneCNS disorders including Alzheimer's disease, addiction, depression and schizophrenia.

Targeting the Neuronal Calcium Sensor (NCS) Protein, VILIP

Heinz Braunewell


1 (visinin-like protein 1, gene name VSNL1) is a member of the NCS family of EFbinding proteins, and has been implicated in Alzheimer’s disease (AD). Lower expression of VILIPprotein and mRNA were found in hippocampus, amygdala, cingreduced expression levels correlate with neurofibrillar tangle content and the MMSE (mini mental statusexamination) score. Increased cerebrospinal fluid content of VILIP

e biomarker for AD. The most recent study in 2011 concluded that CSF VILIPoffer diagnostic utility for early AD, and can predict future cognitive impairment in cognitively normalindividuals similarly to tau/Aβ42. Several lines of experexpression of VILIP-1 and cognitive impairments. For instance, VILIPpathways implicated in synaptic plasticity and memory, and one of its targets, the

line receptor, has been frequently linked to learning and memory processes as well as tocognitive decline in AD. We have used the available knowledge on VILIPassays for chemical compounds modulating functional activity ofdevelop activators of VILIP

1 likely plays a role in disease mechanisms of cognitive deficits, and therefore, comprises a novelial drug target for treatment of such cognitive impairments in neurodegnerative disorders and in the

ageing population.


Heinz Braunewell, PhD

Dr. Braunewell obtained hisM. Schachner) at the Federal Institute of Technology in Zurich, Switzerland, and receivedfurther postdoctoral research training at the Department for NeurochemistrBiology (Prof. E.D. Gundelfinger), LeibnizGermany. In 1998, Dr. Braunewell became head of the Signal Transduction ResearchGroup at the LeibnizMedical Faculty of the Ottoheaded the Signal Transduction Research Group at the Neuroscience Research Center

(NWFZ) of the Charité, Berlin and later became Assistant and Adjunct ProfeInstitute, Medical Faculty, Charité, at Humboldt University in Berlin. Dr. Braunewell joined

Southern Research in 2006, where he is currently an independent PI in the Biochemistry and Molecularof the Drug Discovery Division. He is also a member of the faculty at the

Comprehensive Neuroscience Center (CNC) at The University of Alabama at Birmingham(UAB).Throughout his research career, Dr. Braunewell has focused on molecular and cellular mechanisunderlying brain function, particularly learning and memory. His current interest focuses on the role ofneuronal calcium sensors and nicotinic acetylcholine receptors in addiction, schizophrenia and Alzheimer’sdisease. At Southern Research, Dr. BrauneCNS disorders including Alzheimer's disease, addiction, depression and schizophrenia.


Southern Research Institute, Birmingham, AL

like protein 1, gene name VSNL1) is a member of the NCS family of EFbinding proteins, and has been implicated in Alzheimer’s disease (AD). Lower expression of VILIPprotein and mRNA were found in hippocampus, amygdala, cingreduced expression levels correlate with neurofibrillar tangle content and the MMSE (mini mental statusexamination) score. Increased cerebrospinal fluid content of VILIP

e biomarker for AD. The most recent study in 2011 concluded that CSF VILIPoffer diagnostic utility for early AD, and can predict future cognitive impairment in cognitively normalindividuals similarly to tau/Aβ42. Several lines of exper

1 and cognitive impairments. For instance, VILIPpathways implicated in synaptic plasticity and memory, and one of its targets, the

line receptor, has been frequently linked to learning and memory processes as well as tocognitive decline in AD. We have used the available knowledge on VILIPassays for chemical compounds modulating functional activity ofdevelop activators of VILIP-1 function for further analysis in cognitive tests in AD animal models. Thus,


, PhD, Southern Research Institute

Dr. Braunewell obtained his PhDM. Schachner) at the Federal Institute of Technology in Zurich, Switzerland, and receivedfurther postdoctoral research training at the Department for NeurochemistrBiology (Prof. E.D. Gundelfinger), LeibnizGermany. In 1998, Dr. Braunewell became head of the Signal Transduction ResearchGroup at the Leibniz-Institute for Neurobiology, and he was Lecturer in BiochemMedical Faculty of the Otto-vonheaded the Signal Transduction Research Group at the Neuroscience Research Center

(NWFZ) of the Charité, Berlin and later became Assistant and Adjunct ProfeInstitute, Medical Faculty, Charité, at Humboldt University in Berlin. Dr. Braunewell joined


Comprehensive Neuroscience Center (CNC) at The University of Alabama at Birmingham(UAB).Throughout his research career, Dr. Braunewell has focused on molecular and cellular mechanisunderlying brain function, particularly learning and memory. His current interest focuses on the role ofneuronal calcium sensors and nicotinic acetylcholine receptors in addiction, schizophrenia and Alzheimer’sdisease. At Southern Research, Dr. Braunewell is actively involved in drug discovery for targets in severalCNS disorders including Alzheimer's disease, addiction, depression and schizophrenia.


Birmingham, AL


e biomarker for AD. The most recent study in 2011 concluded that CSF VILIPoffer diagnostic utility for early AD, and can predict future cognitive impairment in cognitively normalindividuals similarly to tau/Aβ42. Several lines of exper


line receptor, has been frequently linked to learning and memory processes as well as tocognitive decline in AD. We have used the available knowledge on VILIPassays for chemical compounds modulating functional activity of

1 function for further analysis in cognitive tests in AD animal models. Thus,1 likely plays a role in disease mechanisms of cognitive deficits, and therefore, comprises a novelial drug target for treatment of such cognitive impairments in neurodegnerative disorders and in the


PhD in Biology in 1993 at the Institute for Neurobiology (Prof.M. Schachner) at the Federal Institute of Technology in Zurich, Switzerland, and receivedfurther postdoctoral research training at the Department for NeurochemistrBiology (Prof. E.D. Gundelfinger), LeibnizGermany. In 1998, Dr. Braunewell became head of the Signal Transduction Research

Institute for Neurobiology, and he was Lecturer in Biochemvon-Guericke University Magdeburg. In 2001, Dr. Braunewell

headed the Signal Transduction Research Group at the Neuroscience Research Center(NWFZ) of the Charité, Berlin and later became Assistant and Adjunct Profe

Institute, Medical Faculty, Charité, at Humboldt University in Berlin. Dr. Braunewell joinedSouthern Research in 2006, where he is currently an independent PI in the Biochemistry and Molecular

of the Drug Discovery Division. He is also a member of the faculty at theComprehensive Neuroscience Center (CNC) at The University of Alabama at Birmingham(UAB).Throughout his research career, Dr. Braunewell has focused on molecular and cellular mechanisunderlying brain function, particularly learning and memory. His current interest focuses on the role ofneuronal calcium sensors and nicotinic acetylcholine receptors in addiction, schizophrenia and Alzheimer’s

well is actively involved in drug discovery for targets in severalCNS disorders including Alzheimer's disease, addiction, depression and schizophrenia.



e biomarker for AD. The most recent study in 2011 concluded that CSF VILIPoffer diagnostic utility for early AD, and can predict future cognitive impairment in cognitively normalindividuals similarly to tau/Aβ42. Several lines of experimental evidence support a link between reduced


line receptor, has been frequently linked to learning and memory processes as well as tocognitive decline in AD. We have used the available knowledge on VILIPassays for chemical compounds modulating functional activity of



in Biology in 1993 at the Institute for Neurobiology (Prof.M. Schachner) at the Federal Institute of Technology in Zurich, Switzerland, and receivedfurther postdoctoral research training at the Department for NeurochemistrBiology (Prof. E.D. Gundelfinger), Leibniz-Institute for Neurobiology in Magdeburg,Germany. In 1998, Dr. Braunewell became head of the Signal Transduction Research

Institute for Neurobiology, and he was Lecturer in BiochemGuericke University Magdeburg. In 2001, Dr. Braunewell

headed the Signal Transduction Research Group at the Neuroscience Research Center(NWFZ) of the Charité, Berlin and later became Assistant and Adjunct Profe




Targeting the Neuronal Calcium Sensor (NCS) Protein, VILIP-1, for Cognitive Impairment in CNS

like protein 1, gene name VSNL1) is a member of the NCS family of EFbinding proteins, and has been implicated in Alzheimer’s disease (AD). Lower expression of VILIPprotein and mRNA were found in hippocampus, amygdala, cingulate and temporal cortex of AD brains. Thereduced expression levels correlate with neurofibrillar tangle content and the MMSE (mini mental statusexamination) score. Increased cerebrospinal fluid content of VILIP-1 (CSF

e biomarker for AD. The most recent study in 2011 concluded that CSF VILIPoffer diagnostic utility for early AD, and can predict future cognitive impairment in cognitively normal

imental evidence support a link between reduced1 and cognitive impairments. For instance, VILIP

pathways implicated in synaptic plasticity and memory, and one of its targets, theline receptor, has been frequently linked to learning and memory processes as well as to

cognitive decline in AD. We have used the available knowledge on VILIPassays for chemical compounds modulating functional activity of VILIP



in Biology in 1993 at the Institute for Neurobiology (Prof.M. Schachner) at the Federal Institute of Technology in Zurich, Switzerland, and receivedfurther postdoctoral research training at the Department for Neurochemistr

Institute for Neurobiology in Magdeburg,Germany. In 1998, Dr. Braunewell became head of the Signal Transduction Research


headed the Signal Transduction Research Group at the Neuroscience Research Center(NWFZ) of the Charité, Berlin and later became Assistant and Adjunct Professor for Physiology at the




1, for Cognitive Impairment in CNS

like protein 1, gene name VSNL1) is a member of the NCS family of EFbinding proteins, and has been implicated in Alzheimer’s disease (AD). Lower expression of VILIP

ulate and temporal cortex of AD brains. Thereduced expression levels correlate with neurofibrillar tangle content and the MMSE (mini mental status

1 (CSF-VILIP-e biomarker for AD. The most recent study in 2011 concluded that CSF VILIP

offer diagnostic utility for early AD, and can predict future cognitive impairment in cognitively normalimental evidence support a link between reduced

1 and cognitive impairments. For instance, VILIP-1 modulates signal transductionpathways implicated in synaptic plasticity and memory, and one of its targets, the

line receptor, has been frequently linked to learning and memory processes as well as tocognitive decline in AD. We have used the available knowledge on VILIP-1 to design cell

VILIP-1. Our goal is to identify and1 function for further analysis in cognitive tests in AD animal models. Thus,


in Biology in 1993 at the Institute for Neurobiology (Prof.M. Schachner) at the Federal Institute of Technology in Zurich, Switzerland, and receivedfurther postdoctoral research training at the Department for Neurochemistr



headed the Signal Transduction Research Group at the Neuroscience Research Centerssor for Physiology at the





like protein 1, gene name VSNL1) is a member of the NCS family of EF-hand calciumbinding proteins, and has been implicated in Alzheimer’s disease (AD). Lower expression of VILIP


-1) was evaluated as ae biomarker for AD. The most recent study in 2011 concluded that CSF VILIP-1 and VILIP


1 modulates signal transductionpathways implicated in synaptic plasticity and memory, and one of its targets, the a4b2

line receptor, has been frequently linked to learning and memory processes as well as to1 to design cell-based screening1. Our goal is to identify and


41

in Biology in 1993 at the Institute for Neurobiology (Prof.M. Schachner) at the Federal Institute of Technology in Zurich, Switzerland, and receivedfurther postdoctoral research training at the Department for Neurochemistry/Molecular


Institute for Neurobiology, and he was Lecturer in Biochemistry at theGuericke University Magdeburg. In 2001, Dr. Braunewell

headed the Signal Transduction Research Group at the Neuroscience Research Centerssor for Physiology at the


of the Drug Discovery Division. He is also a member of the faculty at theComprehensive Neuroscience Center (CNC) at The University of Alabama at Birmingham(UAB).Throughout his research career, Dr. Braunewell has focused on molecular and cellular mechanismsunderlying brain function, particularly learning and memory. His current interest focuses on the role ofneuronal calcium sensors and nicotinic acetylcholine receptors in addiction, schizophrenia and Alzheimer’s

well is actively involved in drug discovery for targets in several


hand calciumbinding proteins, and has been implicated in Alzheimer’s disease (AD). Lower expression of VILIP-1


1) was evaluated as a1 and VILIP-1/Aβ42


1 modulates signal transductiona4b2 nicotinic

line receptor, has been frequently linked to learning and memory processes as well as tobased screening

1. Our goal is to identify and1 function for further analysis in cognitive tests in AD animal models. Thus,


in Biology in 1993 at the Institute for Neurobiology (Prof.M. Schachner) at the Federal Institute of Technology in Zurich, Switzerland, and received

y/MolecularInstitute for Neurobiology in Magdeburg,

Germany. In 1998, Dr. Braunewell became head of the Signal Transduction Researchistry at the

Guericke University Magdeburg. In 2001, Dr. Braunewellheaded the Signal Transduction Research Group at the Neuroscience Research Center

ssor for Physiology at theInstitute, Medical Faculty, Charité, at Humboldt University in Berlin. Dr. Braunewell joined


Comprehensive Neuroscience Center (CNC) at The University of Alabama at Birminghamms

underlying brain function, particularly learning and memory. His current interest focuses on the role ofneuronal calcium sensors and nicotinic acetylcholine receptors in addiction, schizophrenia and Alzheimer’s

well is actively involved in drug discovery for targets in several

hand calcium1


1) was evaluated as a1/Aβ42


1 modulates signal transductionnicotinic

line receptor, has been frequently linked to learning and memory processes as well as tobased screening

1. Our goal is to identify and1 function for further analysis in cognitive tests in AD animal models. Thus,


42

Zhiqun Tan

degeneration with an emphasis on Alzheimer’s disease.Alzheimer’s pathological hallmarks in the retina in both Alzheimer’s transgenic mice and postmortemtissues from AD patients. His research is currently focused on understanding Alzheimer’s lesions in theretina asHe is also highly motivated to develop therapeutic strategies for the treatment of neurodegenerativedisorders using naturopathic compounds. In this regard, histetramethylpyrazine, a small molecule from chuanxiong (a traditional Chinese medicine), for bothimprovement of cognitive function and amelioration of pathological lesions in the brain and eye inAlzheimer’s transgepotential therapeutic use for Alzheimer’s and other neurodegenerative diseases

Efficacy of Herbal Extract, Tetramethylpyrazine, for Alzheimer’s Disease

Zhiqun TanSchreiber

1Departments of Neurology,Neurological Disorders, University of California Irvine School oVA Long Beach Healthcare System, Long Beach, CA

For more than 2500 years herbal preparations have been widely used in traditional Chinese medicine(TCM) for the purposes of general health care and treatment of a variety of diseases. Hundreds of differentherbal species with demonstrated neuroprotectiveneurological disorders including dementia. Among the advantages of purified phytochemicals, which arethe active components of herbs, are stability proven in the ambient environment and ability to cross theblooincreasingly promising as therapeutic candidates for neural protection and the treatment of Alzheimer’sdisease (AD).

Tetramethylpyrazine (TMP), also called as lthe Chinese medicinal herb,chuanxiongExperimental evidence indicates that TMP is an anticapacity to block calcium influx into cells. In this stuAlzheimer’s transgenic mouse models, i.e., 3xTgcompounds, i.e., chemicallyBoth ADEquivalent numbers of AD and WT littermates fed identical chow without TMP were used as controls. After60Morris water maze (MWM) for spatial learning. Mice were then euthanized and both the brain and eyesremoved for histopathological and biochemical analyses. As expected, both 3xTgand 5xFADand MWM results. In contrast, treatment with synthetic TMP, but not herb

Zhiqun Tan

degeneration with an emphasis on Alzheimer’s disease.Alzheimer’s pathological hallmarks in the retina in both Alzheimer’s transgenic mice and postmortemtissues from AD patients. His research is currently focused on understanding Alzheimer’s lesions in theretina as a biomarker for an assessment of the disease activity through a nonHe is also highly motivated to develop therapeutic strategies for the treatment of neurodegenerativedisorders using naturopathic compounds. In this regard, histetramethylpyrazine, a small molecule from chuanxiong (a traditional Chinese medicine), for bothimprovement of cognitive function and amelioration of pathological lesions in the brain and eye inAlzheimer’s transgepotential therapeutic use for Alzheimer’s and other neurodegenerative diseases


Zhiqun Tan1,2

Schreiber1,2,3,4

Departments of Neurology,Neurological Disorders, University of California Irvine School oVA Long Beach Healthcare System, Long Beach, CA

For more than 2500 years herbal preparations have been widely used in traditional Chinese medicine(TCM) for the purposes of general health care and treatment of a variety of diseases. Hundreds of differentherbal species with demonstrated neuroprotectiveneurological disorders including dementia. Among the advantages of purified phytochemicals, which arethe active components of herbs, are stability proven in the ambient environment and ability to cross theblood-brain barrier following oral administration. Therefore naturopathic compounds are becomingincreasingly promising as therapeutic candidates for neural protection and the treatment of Alzheimer’sdisease (AD).

Tetramethylpyrazine (TMP), also called as lthe Chinese medicinal herb,chuanxiong has been used as a therapeutic for heart, kidney and brain diseases by practitioners of TCM.Experimental evidence indicates that TMP is an anticapacity to block calcium influx into cells. In this stuAlzheimer’s transgenic mouse models, i.e., 3xTgcompounds, i.e., chemicallyBoth AD and wild type (WT) mice were fed chow containing either synthetic or natural TMP (300 mg/kg).Equivalent numbers of AD and WT littermates fed identical chow without TMP were used as controls. After60-80 days animals were tested in a novel object recognitMorris water maze (MWM) for spatial learning. Mice were then euthanized and both the brain and eyesremoved for histopathological and biochemical analyses. As expected, both 3xTgand 5xFAD (6and MWM results. In contrast, treatment with synthetic TMP, but not herb

Zhiqun Tan, MD, PhD,

Zhiqun Tan is an Associate Research Professor in the Department of Neurology andInstitute for Memory Impairments and Neurological Disorders (iMIND) at University ofCalifornia Irvine School of Medicine. He received hisUniversity,Wuhan University in China. Then he worked as a faculty member at Wuhan University inthe field of environmental toxicology. 1996 he moved toa research neuroscientist at University of Southern California Keck School of Medicine. Hejoined the faculty of UCI Neurology in 2002 and has been studying on neuronal

degeneration with an emphasis on Alzheimer’s disease.Alzheimer’s pathological hallmarks in the retina in both Alzheimer’s transgenic mice and postmortemtissues from AD patients. His research is currently focused on understanding Alzheimer’s lesions in the

a biomarker for an assessment of the disease activity through a nonHe is also highly motivated to develop therapeutic strategies for the treatment of neurodegenerativedisorders using naturopathic compounds. In this regard, histetramethylpyrazine, a small molecule from chuanxiong (a traditional Chinese medicine), for bothimprovement of cognitive function and amelioration of pathological lesions in the brain and eye inAlzheimer’s transgenic mice. He is evaluating more compounds from known herbal medicines for thepotential therapeutic use for Alzheimer’s and other neurodegenerative diseases


1,2, Wayne W. Poon1,2,3,4

Departments of Neurology,Neurological Disorders, University of California Irvine School oVA Long Beach Healthcare System, Long Beach, CA

For more than 2500 years herbal preparations have been widely used in traditional Chinese medicine(TCM) for the purposes of general health care and treatment of a variety of diseases. Hundreds of differentherbal species with demonstrated neuroprotectiveneurological disorders including dementia. Among the advantages of purified phytochemicals, which arethe active components of herbs, are stability proven in the ambient environment and ability to cross the

brain barrier following oral administration. Therefore naturopathic compounds are becomingincreasingly promising as therapeutic candidates for neural protection and the treatment of Alzheimer’sdisease (AD).

Tetramethylpyrazine (TMP), also called as lthe Chinese medicinal herb,

has been used as a therapeutic for heart, kidney and brain diseases by practitioners of TCM.Experimental evidence indicates that TMP is an anticapacity to block calcium influx into cells. In this stuAlzheimer’s transgenic mouse models, i.e., 3xTgcompounds, i.e., chemically

and wild type (WT) mice were fed chow containing either synthetic or natural TMP (300 mg/kg).Equivalent numbers of AD and WT littermates fed identical chow without TMP were used as controls. After

80 days animals were tested in a novel object recognitMorris water maze (MWM) for spatial learning. Mice were then euthanized and both the brain and eyesremoved for histopathological and biochemical analyses. As expected, both 3xTg

(6-month old) mice had considerable deficits in learning and memory as revealed by NORTand MWM results. In contrast, treatment with synthetic TMP, but not herb

PhD, University of California, Irvine

Zhiqun Tan is an Associate Research Professor in the Department of Neurology andInstitute for Memory Impairments and Neurological Disorders (iMIND) at University ofCalifornia Irvine School of Medicine. He received hisUniversity, BSc in Biochemistry in 1987 andWuhan University in China. Then he worked as a faculty member at Wuhan University inthe field of environmental toxicology. 1996 he moved toa research neuroscientist at University of Southern California Keck School of Medicine. Hejoined the faculty of UCI Neurology in 2002 and has been studying on neuronal


a biomarker for an assessment of the disease activity through a nonHe is also highly motivated to develop therapeutic strategies for the treatment of neurodegenerativedisorders using naturopathic compounds. In this regard, histetramethylpyrazine, a small molecule from chuanxiong (a traditional Chinese medicine), for bothimprovement of cognitive function and amelioration of pathological lesions in the brain and eye in

nic mice. He is evaluating more compounds from known herbal medicines for thepotential therapeutic use for Alzheimer’s and other neurodegenerative diseases


W. Poon2, Emily Wu

Departments of Neurology, 2Anatomy and Neurobiology, andNeurological Disorders, University of California Irvine School oVA Long Beach Healthcare System, Long Beach, CA


brain barrier following oral administration. Therefore naturopathic compounds are becomingincreasingly promising as therapeutic candidates for neural protection and the treatment of Alzheimer’s

Tetramethylpyrazine (TMP), also called as lthe Chinese medicinal herb, Ligusticum wallichii

has been used as a therapeutic for heart, kidney and brain diseases by practitioners of TCM.Experimental evidence indicates that TMP is an anticapacity to block calcium influx into cells. In this stuAlzheimer’s transgenic mouse models, i.e., 3xTgcompounds, i.e., chemically-synthesized TMP and herb


80 days animals were tested in a novel object recognitMorris water maze (MWM) for spatial learning. Mice were then euthanized and both the brain and eyesremoved for histopathological and biochemical analyses. As expected, both 3xTg

month old) mice had considerable deficits in learning and memory as revealed by NORTand MWM results. In contrast, treatment with synthetic TMP, but not herb

University of California, Irvine

Zhiqun Tan is an Associate Research Professor in the Department of Neurology andInstitute for Memory Impairments and Neurological Disorders (iMIND) at University ofCalifornia Irvine School of Medicine. He received his

in Biochemistry in 1987 andWuhan University in China. Then he worked as a faculty member at Wuhan University inthe field of environmental toxicology. 1996 he moved toa research neuroscientist at University of Southern California Keck School of Medicine. Hejoined the faculty of UCI Neurology in 2002 and has been studying on neuronal





, Emily Wu1, Scott Chen

Anatomy and Neurobiology, andNeurological Disorders, University of California Irvine School oVA Long Beach Healthcare System, Long Beach, CA



Tetramethylpyrazine (TMP), also called as ligustrazine, is an alkaloid originally isolated from the rhizome ofLigusticum wallichii Franchat (

has been used as a therapeutic for heart, kidney and brain diseases by practitioners of TCM.Experimental evidence indicates that TMP is an anticapacity to block calcium influx into cells. In this stuAlzheimer’s transgenic mouse models, i.e., 3xTg

synthesized TMP and herband wild type (WT) mice were fed chow containing either synthetic or natural TMP (300 mg/kg).

Equivalent numbers of AD and WT littermates fed identical chow without TMP were used as controls. After80 days animals were tested in a novel object recognit

Morris water maze (MWM) for spatial learning. Mice were then euthanized and both the brain and eyesremoved for histopathological and biochemical analyses. As expected, both 3xTg



Zhiqun Tan is an Associate Research Professor in the Department of Neurology andInstitute for Memory Impairments and Neurological Disorders (iMIND) at University ofCalifornia Irvine School of Medicine. He received his

in Biochemistry in 1987 andWuhan University in China. Then he worked as a faculty member at Wuhan University inthe field of environmental toxicology. 1996 he moved toa research neuroscientist at University of Southern California Keck School of Medicine. Hejoined the faculty of UCI Neurology in 2002 and has been studying on neuronal





, Scott Chen1, Stacey Lee

Anatomy and Neurobiology, andNeurological Disorders, University of California Irvine School oVA Long Beach Healthcare System, Long Beach, CA

For more than 2500 years herbal preparations have been widely used in traditional Chinese medicine(TCM) for the purposes of general health care and treatment of a variety of diseases. Hundreds of differentherbal species with demonstrated neuroprotective efficacy have been used for the treatment ofneurological disorders including dementia. Among the advantages of purified phytochemicals, which arethe active components of herbs, are stability proven in the ambient environment and ability to cross the


igustrazine, is an alkaloid originally isolated from the rhizome ofFranchat (chuanxiong

has been used as a therapeutic for heart, kidney and brain diseases by practitioners of TCM.Experimental evidence indicates that TMP is an anti-inflammatory and anticapacity to block calcium influx into cells. In this study, we tested the efficacy of TMP in two different

-AD and 5xFAD mice. The therapeutic efficacy of twosynthesized TMP and herb-derived TMP, were tested in these two models.


80 days animals were tested in a novel object recognition task (NORT) for shortMorris water maze (MWM) for spatial learning. Mice were then euthanized and both the brain and eyesremoved for histopathological and biochemical analyses. As expected, both 3xTg



Zhiqun Tan is an Associate Research Professor in the Department of Neurology andInstitute for Memory Impairments and Neurological Disorders (iMIND) at University ofCalifornia Irvine School of Medicine. He received his MD

in Biochemistry in 1987 and PhD in Biological Chemistry in 1993 fromWuhan University in China. Then he worked as a faculty member at Wuhan University inthe field of environmental toxicology. 1996 he moved toa research neuroscientist at University of Southern California Keck School of Medicine. Hejoined the faculty of UCI Neurology in 2002 and has been studying on neuronal

degeneration with an emphasis on Alzheimer’s disease. Dr. Tan’s group has recently identifiedAlzheimer’s pathological hallmarks in the retina in both Alzheimer’s transgenic mice and postmortemtissues from AD patients. His research is currently focused on understanding Alzheimer’s lesions in the

a biomarker for an assessment of the disease activity through a nonHe is also highly motivated to develop therapeutic strategies for the treatment of neurodegenerativedisorders using naturopathic compounds. In this regard, his recent work has demonstrated efficacy oftetramethylpyrazine, a small molecule from chuanxiong (a traditional Chinese medicine), for bothimprovement of cognitive function and amelioration of pathological lesions in the brain and eye in



, Stacey Lee1, Carl W. Cotman

Anatomy and Neurobiology, and 3Institute for Memory Impairments andNeurological Disorders, University of California Irvine School of Medicine, Irvine, CA;

For more than 2500 years herbal preparations have been widely used in traditional Chinese medicine(TCM) for the purposes of general health care and treatment of a variety of diseases. Hundreds of different

efficacy have been used for the treatment ofneurological disorders including dementia. Among the advantages of purified phytochemicals, which arethe active components of herbs, are stability proven in the ambient environment and ability to cross the


igustrazine, is an alkaloid originally isolated from the rhizome ofchuanxiong). For hundreds of years,

has been used as a therapeutic for heart, kidney and brain diseases by practitioners of TCM.inflammatory and anti

dy, we tested the efficacy of TMP in two differentAD and 5xFAD mice. The therapeutic efficacy of two

derived TMP, were tested in these two models.and wild type (WT) mice were fed chow containing either synthetic or natural TMP (300 mg/kg).

Equivalent numbers of AD and WT littermates fed identical chow without TMP were used as controls. Afterion task (NORT) for short

Morris water maze (MWM) for spatial learning. Mice were then euthanized and both the brain and eyesremoved for histopathological and biochemical analyses. As expected, both 3xTg


Zhiqun Tan is an Associate Research Professor in the Department of Neurology andInstitute for Memory Impairments and Neurological Disorders (iMIND) at University of

MD (BM) in 1985 from Tongji Medicalin Biological Chemistry in 1993 from

Wuhan University in China. Then he worked as a faculty member at Wuhan University inthe field of environmental toxicology. 1996 he moved to the United Stated and trained asa research neuroscientist at University of Southern California Keck School of Medicine. Hejoined the faculty of UCI Neurology in 2002 and has been studying on neuronal

Dr. Tan’s group has recently identifiedAlzheimer’s pathological hallmarks in the retina in both Alzheimer’s transgenic mice and postmortemtissues from AD patients. His research is currently focused on understanding Alzheimer’s lesions in the

a biomarker for an assessment of the disease activity through a non-invasive imaging approach.He is also highly motivated to develop therapeutic strategies for the treatment of neurodegenerative

recent work has demonstrated efficacy oftetramethylpyrazine, a small molecule from chuanxiong (a traditional Chinese medicine), for bothimprovement of cognitive function and amelioration of pathological lesions in the brain and eye in

nic mice. He is evaluating more compounds from known herbal medicines for thepotential therapeutic use for Alzheimer’s and other neurodegenerative diseases.


, Carl W. Cotman

Institute for Memory Impairments andf Medicine, Irvine, CA;




igustrazine, is an alkaloid originally isolated from the rhizome of). For hundreds of years,

has been used as a therapeutic for heart, kidney and brain diseases by practitioners of TCM.inflammatory and anti-oxidant small molecule with the



Equivalent numbers of AD and WT littermates fed identical chow without TMP were used as controls. Afterion task (NORT) for short-term memory and the

Morris water maze (MWM) for spatial learning. Mice were then euthanized and both the brain and eyesremoved for histopathological and biochemical analyses. As expected, both 3xTg-AD (12~14

month old) mice had considerable deficits in learning and memory as revealed by NORTand MWM results. In contrast, treatment with synthetic TMP, but not herb-derived TMP, significantly


) in 1985 from Tongji Medicalin Biological Chemistry in 1993 from

Wuhan University in China. Then he worked as a faculty member at Wuhan University inthe United Stated and trained as

a research neuroscientist at University of Southern California Keck School of Medicine. Hejoined the faculty of UCI Neurology in 2002 and has been studying on neuronal


invasive imaging approach.He is also highly motivated to develop therapeutic strategies for the treatment of neurodegenerative


nic mice. He is evaluating more compounds from known herbal medicines for the

, Carl W. Cotman1,3, Steven S.

Institute for Memory Impairments andf Medicine, Irvine, CA; 4Neurology Section,





has been used as a therapeutic for heart, kidney and brain diseases by practitioners of TCM.oxidant small molecule with the



Equivalent numbers of AD and WT littermates fed identical chow without TMP were used as controls. Afterterm memory and the

Morris water maze (MWM) for spatial learning. Mice were then euthanized and both the brain and eyesAD (12~14-month old)

month old) mice had considerable deficits in learning and memory as revealed by NORTderived TMP, significantly









, Steven S.

Institute for Memory Impairments andNeurology Section,


neurological disorders including dementia. Among the advantages of purified phytochemicals, which arethe active components of herbs, are stability proven in the ambient environment and ability to cross the



has been used as a therapeutic for heart, kidney and brain diseases by practitioners of TCM.oxidant small molecule with the



Equivalent numbers of AD and WT littermates fed identical chow without TMP were used as controls. Afterterm memory and the

Morris water maze (MWM) for spatial learning. Mice were then euthanized and both the brain and eyesmonth old)

month old) mice had considerable deficits in learning and memory as revealed by NORTderived TMP, significantly









igustrazine, is an alkaloid originally isolated from the rhizome of


improved cognitive performance in both lines of AD mice. Notably, there was a significant reduction in beta-amyloid plaques and neuroinflammatory markers in the brain and retina of mice treated with either form ofTMP. Further analysis demonstrated decreased amounts of lipid peroxidation products as well asoligomeric forms of beta-amyloid in brain lysates from TMP-treated mice. We conclude that TMP reducesbeta-amyloid and neuroinflammation in both the brain and retina and ameliorates cognitive dysfunction inAD mice. Moreover, our results suggest that natural preparations of phytochemicals may be lessefficacious than their synthetic counterparts.

Acknowledgements: This study is supported by the Alzheimer’s Drug Discovery Foundation.

44

IV. Accelerating Clinical Trials for Alzheimer’s Disease through BiomarkersChair: Tim West, PhD, C2N Diagnostics

A Novel Application of Stable Isotope Labeling for Disease Detection and Clinical Trials inAlzheimer’sTim West, PhD, C2N Diagnostics

TOMM40 Genetic Biomarker: Accelerating Drug Development for Alzheimer’s Disease andFrontotemporal DementiaAllen D. Roses, FRCP (hon.), MD, Duke University

CSF Biomarkers of FTLD-TDP and FTLD-Tau: A Multi-Center StudyWilliam Hu, MD, PhD, Emory University School of Medicine

Use of Targeted Multiplex Proteomic Strategies to Identify Plasma and Cerebral Spinal Fluid-BasedBiomarkers in Alzheimer’s DiseaseJudith Siuciak, PhD, The Biomarkers Consortium, Foundation for the National Institutes of Health

Pilot Trial of Metformin in the Prevention of Alzheimer’s DiseaseJosé A. Luchsinger, MD, MPH, Columbia University


Tim West

the Vice Presidenttransference of the SILK technology to the company, and implemented quality controls and systems withinthe company. Dr. West has also led C2N’s research and development efforts in the proteomicmeasurement of other proteins implicated in neurodegeneration. He has served as a director to multipleclinical studies using the SILK technology. In addition, DInvestigator on numerous grants awarded from multiple private foundation and public sources of supportfor funding.

A Novel Application of Stable Isotope Labeling for Disease Detection and Clinical Trials inAlzheimer’s

Tim West

C2N Diagnostics

One of the hallmarks of Alzheimer's disease (AD) is the presence of amyloid plaques in the brain. One ofthe main constituents of the plaques is the peptide amyloid beta. Over the last decade,animals and humans have pointed to plaques as a leading cause for the progression of Alzheimer'sdisease and research in humans have shown that amyloid plaques are most likely present in the brain longbefore any clinical signs of Alzheimer'sclear over the past decade that in order to develop disease modifying therapeutics that can prevent or slowdown the progression of AD it is important to have the right tools for diagnosis andensure that you are enrolling the right population in your clinical trials. Especially as the focus is shiftingtowards treating the early stages of the disease or disease prevention this becomes exceedingly important.

Ideallycertain procedures with the C2N proprietary stable isotope labeling methods, C2N hopes to create a bloodbased diagnostic test that can assess the levels ofdiagnosis of Alzheimer's disease. If this test translates to humans it will greatly aid in the clinical trials foramyloid plaque modifying therapeutics and once such drugs get approved this test couldscreening test to select people that should be on such drugs.


Tim West, PhD,

the Vice Presidenttransference of the SILK technology to the company, and implemented quality controls and systems withinthe company. Dr. West has also led C2N’s research and development efforts in the proteomicmeasurement of other proteins implicated in neurodegeneration. He has served as a director to multipleclinical studies using the SILK technology. In addition, DInvestigator on numerous grants awarded from multiple private foundation and public sources of supportfor funding.

A Novel Application of Stable Isotope Labeling for Disease Detection and Clinical Trials inAlzheimer’s

Tim West

C2N Diagnostics


Ideally a diagnostic test for AD would be easy to administer and have high predictive value. By combiningcertain procedures with the C2N proprietary stable isotope labeling methods, C2N hopes to create a bloodbased diagnostic test that can assess the levels ofdiagnosis of Alzheimer's disease. If this test translates to humans it will greatly aid in the clinical trials foramyloid plaque modifying therapeutics and once such drugs get approved this test couldscreening test to select people that should be on such drugs.


, PhD, C2N Diagnostics

Dr. Tim West graduated from the Washington University School of Medicine in 2006 with aPhD in Neuroscience and Molecular &laboratory of Dr. David Holtzman within the Department of Neurology, involvedinvestigating the mechanisms of cell death after ischemic stroke in newborns. Followingthe completion of hisScientist in Dr. Holtzman’s laboratory. He also served as the Assistant Director ofTechnology Development for the Hope Center for Neurological Disorders. Dr. West joinedC2N Diagnostics in November, 2007

the Vice President of Research and Development. During his time at C2N, Dr. West has overseen thetransference of the SILK technology to the company, and implemented quality controls and systems withinthe company. Dr. West has also led C2N’s research and development efforts in the proteomicmeasurement of other proteins implicated in neurodegeneration. He has served as a director to multipleclinical studies using the SILK technology. In addition, DInvestigator on numerous grants awarded from multiple private foundation and public sources of support

A Novel Application of Stable Isotope Labeling for Disease Detection and Clinical Trials in

C2N Diagnostics, St. Louis, MO


a diagnostic test for AD would be easy to administer and have high predictive value. By combiningcertain procedures with the C2N proprietary stable isotope labeling methods, C2N hopes to create a bloodbased diagnostic test that can assess the levels ofdiagnosis of Alzheimer's disease. If this test translates to humans it will greatly aid in the clinical trials foramyloid plaque modifying therapeutics and once such drugs get approved this test couldscreening test to select people that should be on such drugs.


C2N Diagnostics

Dr. Tim West graduated from the Washington University School of Medicine in 2006 with ain Neuroscience and Molecular &

laboratory of Dr. David Holtzman within the Department of Neurology, involvedinvestigating the mechanisms of cell death after ischemic stroke in newborns. Followingthe completion of hisScientist in Dr. Holtzman’s laboratory. He also served as the Assistant Director ofTechnology Development for the Hope Center for Neurological Disorders. Dr. West joinedC2N Diagnostics in November, 2007

of Research and Development. During his time at C2N, Dr. West has overseen thetransference of the SILK technology to the company, and implemented quality controls and systems withinthe company. Dr. West has also led C2N’s research and development efforts in the proteomicmeasurement of other proteins implicated in neurodegeneration. He has served as a director to multipleclinical studies using the SILK technology. In addition, DInvestigator on numerous grants awarded from multiple private foundation and public sources of support


St. Louis, MO



C2N Diagnostics

Dr. Tim West graduated from the Washington University School of Medicine in 2006 with ain Neuroscience and Molecular &

laboratory of Dr. David Holtzman within the Department of Neurology, involvedinvestigating the mechanisms of cell death after ischemic stroke in newborns. Followingthe completion of his PhD, Dr. WestScientist in Dr. Holtzman’s laboratory. He also served as the Assistant Director ofTechnology Development for the Hope Center for Neurological Disorders. Dr. West joinedC2N Diagnostics in November, 2007

of Research and Development. During his time at C2N, Dr. West has overseen thetransference of the SILK technology to the company, and implemented quality controls and systems withinthe company. Dr. West has also led C2N’s research and development efforts in the proteomicmeasurement of other proteins implicated in neurodegeneration. He has served as a director to multipleclinical studies using the SILK technology. In addition, DInvestigator on numerous grants awarded from multiple private foundation and public sources of support


One of the hallmarks of Alzheimer's disease (AD) is the presence of amyloid plaques in the brain. One ofthe main constituents of the plaques is the peptide amyloid beta. Over the last decade,animals and humans have pointed to plaques as a leading cause for the progression of Alzheimer'sdisease and research in humans have shown that amyloid plaques are most likely present in the brain longbefore any clinical signs of Alzheimer's disease (such as memory loss) are present. It has also becomeclear over the past decade that in order to develop disease modifying therapeutics that can prevent or slowdown the progression of AD it is important to have the right tools for diagnosis andensure that you are enrolling the right population in your clinical trials. Especially as the focus is shiftingtowards treating the early stages of the disease or disease prevention this becomes exceedingly important.


Dr. Tim West graduated from the Washington University School of Medicine in 2006 with ain Neuroscience and Molecular & Cellular Biology. His thesis work, completed in the

laboratory of Dr. David Holtzman within the Department of Neurology, involvedinvestigating the mechanisms of cell death after ischemic stroke in newborns. Following

, Dr. West served as a PostScientist in Dr. Holtzman’s laboratory. He also served as the Assistant Director ofTechnology Development for the Hope Center for Neurological Disorders. Dr. West joinedC2N Diagnostics in November, 2007 as the Director of Laboratory

of Research and Development. During his time at C2N, Dr. West has overseen thetransference of the SILK technology to the company, and implemented quality controls and systems withinthe company. Dr. West has also led C2N’s research and development efforts in the proteomicmeasurement of other proteins implicated in neurodegeneration. He has served as a director to multipleclinical studies using the SILK technology. In addition, Dr. West has served as the Company’s PrincipalInvestigator on numerous grants awarded from multiple private foundation and public sources of support


One of the hallmarks of Alzheimer's disease (AD) is the presence of amyloid plaques in the brain. One ofthe main constituents of the plaques is the peptide amyloid beta. Over the last decade,animals and humans have pointed to plaques as a leading cause for the progression of Alzheimer'sdisease and research in humans have shown that amyloid plaques are most likely present in the brain long

disease (such as memory loss) are present. It has also becomeclear over the past decade that in order to develop disease modifying therapeutics that can prevent or slowdown the progression of AD it is important to have the right tools for diagnosis andensure that you are enrolling the right population in your clinical trials. Especially as the focus is shiftingtowards treating the early stages of the disease or disease prevention this becomes exceedingly important.

a diagnostic test for AD would be easy to administer and have high predictive value. By combiningcertain procedures with the C2N proprietary stable isotope labeling methods, C2N hopes to create a bloodbased diagnostic test that can assess the levels of plaque in the brain and may thus allow prediagnosis of Alzheimer's disease. If this test translates to humans it will greatly aid in the clinical trials foramyloid plaque modifying therapeutics and once such drugs get approved this test couldscreening test to select people that should be on such drugs.

Dr. Tim West graduated from the Washington University School of Medicine in 2006 with aCellular Biology. His thesis work, completed in the


served as a PostScientist in Dr. Holtzman’s laboratory. He also served as the Assistant Director ofTechnology Development for the Hope Center for Neurological Disorders. Dr. West joined

as the Director of Laboratoryof Research and Development. During his time at C2N, Dr. West has overseen the

transference of the SILK technology to the company, and implemented quality controls and systems withinthe company. Dr. West has also led C2N’s research and development efforts in the proteomicmeasurement of other proteins implicated in neurodegeneration. He has served as a director to multiple

r. West has served as the Company’s PrincipalInvestigator on numerous grants awarded from multiple private foundation and public sources of support



disease (such as memory loss) are present. It has also becomeclear over the past decade that in order to develop disease modifying therapeutics that can prevent or slowdown the progression of AD it is important to have the right tools for diagnosis andensure that you are enrolling the right population in your clinical trials. Especially as the focus is shiftingtowards treating the early stages of the disease or disease prevention this becomes exceedingly important.

a diagnostic test for AD would be easy to administer and have high predictive value. By combiningcertain procedures with the C2N proprietary stable isotope labeling methods, C2N hopes to create a blood

plaque in the brain and may thus allow prediagnosis of Alzheimer's disease. If this test translates to humans it will greatly aid in the clinical trials foramyloid plaque modifying therapeutics and once such drugs get approved this test couldscreening test to select people that should be on such drugs.



served as a Post-Doctoral Fellow and later StaffScientist in Dr. Holtzman’s laboratory. He also served as the Assistant Director ofTechnology Development for the Hope Center for Neurological Disorders. Dr. West joined

as the Director of Laboratory Operations and later asof Research and Development. During his time at C2N, Dr. West has overseen the





disease (such as memory loss) are present. It has also becomeclear over the past decade that in order to develop disease modifying therapeutics that can prevent or slowdown the progression of AD it is important to have the right tools for diagnosis and staging of AD in order toensure that you are enrolling the right population in your clinical trials. Especially as the focus is shiftingtowards treating the early stages of the disease or disease prevention this becomes exceedingly important.


plaque in the brain and may thus allow prediagnosis of Alzheimer's disease. If this test translates to humans it will greatly aid in the clinical trials foramyloid plaque modifying therapeutics and once such drugs get approved this test could



Doctoral Fellow and later StaffScientist in Dr. Holtzman’s laboratory. He also served as the Assistant Director ofTechnology Development for the Hope Center for Neurological Disorders. Dr. West joined

Operations and later asof Research and Development. During his time at C2N, Dr. West has overseen the




One of the hallmarks of Alzheimer's disease (AD) is the presence of amyloid plaques in the brain. One ofthe main constituents of the plaques is the peptide amyloid beta. Over the last decade, research fromanimals and humans have pointed to plaques as a leading cause for the progression of Alzheimer'sdisease and research in humans have shown that amyloid plaques are most likely present in the brain long

disease (such as memory loss) are present. It has also becomeclear over the past decade that in order to develop disease modifying therapeutics that can prevent or slow

staging of AD in order toensure that you are enrolling the right population in your clinical trials. Especially as the focus is shiftingtowards treating the early stages of the disease or disease prevention this becomes exceedingly important.


plaque in the brain and may thus allow prediagnosis of Alzheimer's disease. If this test translates to humans it will greatly aid in the clinical trials foramyloid plaque modifying therapeutics and once such drugs get approved this test could be an important

45








One of the hallmarks of Alzheimer's disease (AD) is the presence of amyloid plaques in the brain. One ofresearch from

animals and humans have pointed to plaques as a leading cause for the progression of Alzheimer'sdisease and research in humans have shown that amyloid plaques are most likely present in the brain long


staging of AD in order toensure that you are enrolling the right population in your clinical trials. Especially as the focus is shiftingtowards treating the early stages of the disease or disease prevention this becomes exceedingly important.


plaque in the brain and may thus allow pre-clinicaldiagnosis of Alzheimer's disease. If this test translates to humans it will greatly aid in the clinical trials for

be an important





the company. Dr. West has also led C2N’s research and development efforts in the proteomicmeasurement of other proteins implicated in neurodegeneration. He has served as a director to multiple


One of the hallmarks of Alzheimer's disease (AD) is the presence of amyloid plaques in the brain. One ofresearch from

animals and humans have pointed to plaques as a leading cause for the progression of Alzheimer'sdisease and research in humans have shown that amyloid plaques are most likely present in the brain long


staging of AD in order toensure that you are enrolling the right population in your clinical trials. Especially as the focus is shifting


clinicaldiagnosis of Alzheimer's disease. If this test translates to humans it will greatly aid in the clinical trials for

be an important

46

Allen D. Roses

Discovery Institute, and as Senior Scholar at the Fuqua School of Business.after a decadepredecessor GlaxoWellcome (Gsusceptibilityinto medicine discovery and development. Subsequently at GSK, he headed research in clgenomics, proteomics, pharmacogenetics, and bioinformatics in support of the entire R&D pipeline.

During his previous tenure at Duke, Dr. Roses was Jefferson Pilot Professor of Neurobiology andNeurology, Founding Director of the JosephChief of the Division of Neurology, and Director of the Center for Human Genetics.clinical neurologists to apply molecular genetic strategies to neurological diseases. His lthe chromosomal location for more than 15 diseases, including several muscular dystrophies and LouGehrig’s disease. He led the team that in 1992 identified APOE as a major, widely confirmed susceptibilitygene in common lateanalyses and drug discovery and development continued in GSK.

Dr. Roses was a member of the Science Board of the US Food and Drug Administration between 20032007. He was a member of the Bthe report “FDA Science and Mission at Risk.” He continues to consult with the FDA and other regulatoryagencies in the field of pharmacogenetics and companion diagnostics.

TOMM40 GenetiFrontotemporal Dementia

Allen D. Roses

Duke Univers

TOMM40 is the name for the gene adjacent to APOE on chromosome 19 in LD, contains manypolymorphic markers within[rs10524523] that is linked on the same strand to an APOE genotype variant. Our published work hasdescribed the relationship to the age of onset of symptoms leading to AD betweenvariant on each DNA stand and the APOE variant. We have constructed an algorithm based on TOMM40523 genotypes, APOE genotypes and age that will be tested in combination as a “prognostic biomarker” forthe design of a delay of onset of symptsubjects, as defined by neuropsychological testing. In Alliance with Takeda Pharmaceuticals, we plan toevaluate the effect of pioglitazone in delaying the onset of cognitive impairment oTOMM40can be assessed. This will be done concurrently with the delay of onset trial. The pharmacogeneticenrichment of a highpharmacogenetic biomarker. We have some additional data that may also support the involvement ofTOMM40 in Frontotemporal Dementia as well.

Allen D. Roses

Discovery Institute, and as Senior Scholar at the Fuqua School of Business.after a decadepredecessor GlaxoWellcome (Gsusceptibility-into medicine discovery and development. Subsequently at GSK, he headed research in clgenomics, proteomics, pharmacogenetics, and bioinformatics in support of the entire R&D pipeline.

During his previous tenure at Duke, Dr. Roses was Jefferson Pilot Professor of Neurobiology andNeurology, Founding Director of the JosephChief of the Division of Neurology, and Director of the Center for Human Genetics.clinical neurologists to apply molecular genetic strategies to neurological diseases. His lthe chromosomal location for more than 15 diseases, including several muscular dystrophies and LouGehrig’s disease. He led the team that in 1992 identified APOE as a major, widely confirmed susceptibilitygene in common lateanalyses and drug discovery and development continued in GSK.


TOMM40 GenetiFrontotemporal Dementia

Allen D. Roses

Duke Univers

TOMM40 is the name for the gene adjacent to APOE on chromosome 19 in LD, contains manypolymorphic markers within[rs10524523] that is linked on the same strand to an APOE genotype variant. Our published work hasdescribed the relationship to the age of onset of symptoms leading to AD betweenvariant on each DNA stand and the APOE variant. We have constructed an algorithm based on TOMM40523 genotypes, APOE genotypes and age that will be tested in combination as a “prognostic biomarker” forthe design of a delay of onset of symptsubjects, as defined by neuropsychological testing. In Alliance with Takeda Pharmaceuticals, we plan toevaluate the effect of pioglitazone in delaying the onset of cognitive impairment oTOMM40-523 is not a diagnostic test, or biomarker, for the diagnosis of AD until prospective PPV and NPVcan be assessed. This will be done concurrently with the delay of onset trial. The pharmacogeneticenrichment of a highpharmacogenetic biomarker. We have some additional data that may also support the involvement ofTOMM40 in Frontotemporal Dementia as well.

Allen D. Roses, MD

Allen D. Roses has established an international reputation for his work inpharmacogenetics, exploratory drug discovery, andfounded Cabernet Pharmaceuticals in 2008 to provide pharmacogenetics (PGx) andproject-management services to pharmaceutical and biotechnology companies, clinicalresearch and managedformed a team of consultants with deep experience in the practical application of PGx todrug development.Jefferson

Discovery Institute, and as Senior Scholar at the Fuqua School of Business.after a decade-long career as a Senior Vice President at GlaxoSmithKline (GSK) and its corporatepredecessor GlaxoWellcome (G

-gene discovery, pharmacogenetics strategy and implementation, and integration of geneticsinto medicine discovery and development. Subsequently at GSK, he headed research in clgenomics, proteomics, pharmacogenetics, and bioinformatics in support of the entire R&D pipeline.

During his previous tenure at Duke, Dr. Roses was Jefferson Pilot Professor of Neurobiology andNeurology, Founding Director of the JosephChief of the Division of Neurology, and Director of the Center for Human Genetics.clinical neurologists to apply molecular genetic strategies to neurological diseases. His lthe chromosomal location for more than 15 diseases, including several muscular dystrophies and LouGehrig’s disease. He led the team that in 1992 identified APOE as a major, widely confirmed susceptibilitygene in common late-onset Alzheanalyses and drug discovery and development continued in GSK.


TOMM40 Genetic Biomarker:Frontotemporal Dementia

Allen D. Roses

Duke University, Durham, NC

TOMM40 is the name for the gene adjacent to APOE on chromosome 19 in LD, contains manypolymorphic markers within[rs10524523] that is linked on the same strand to an APOE genotype variant. Our published work hasdescribed the relationship to the age of onset of symptoms leading to AD betweenvariant on each DNA stand and the APOE variant. We have constructed an algorithm based on TOMM40523 genotypes, APOE genotypes and age that will be tested in combination as a “prognostic biomarker” forthe design of a delay of onset of symptsubjects, as defined by neuropsychological testing. In Alliance with Takeda Pharmaceuticals, we plan toevaluate the effect of pioglitazone in delaying the onset of cognitive impairment o

523 is not a diagnostic test, or biomarker, for the diagnosis of AD until prospective PPV and NPVcan be assessed. This will be done concurrently with the delay of onset trial. The pharmacogeneticenrichment of a high-risk popharmacogenetic biomarker. We have some additional data that may also support the involvement ofTOMM40 in Frontotemporal Dementia as well.

D, FRCP (hon

Allen D. Roses has established an international reputation for his work inpharmacogenetics, exploratory drug discovery, andfounded Cabernet Pharmaceuticals in 2008 to provide pharmacogenetics (PGx) and

management services to pharmaceutical and biotechnology companies, clinicalresearch and managedformed a team of consultants with deep experience in the practical application of PGx todrug development.Jefferson-Pilot Professor of Neurobiology and Genetics, as D

Discovery Institute, and as Senior Scholar at the Fuqua School of Business.long career as a Senior Vice President at GlaxoSmithKline (GSK) and its corporate

predecessor GlaxoWellcome (GW). Upon joining GW in 1997, he organized genetic strategies forgene discovery, pharmacogenetics strategy and implementation, and integration of genetics

into medicine discovery and development. Subsequently at GSK, he headed research in clgenomics, proteomics, pharmacogenetics, and bioinformatics in support of the entire R&D pipeline.

During his previous tenure at Duke, Dr. Roses was Jefferson Pilot Professor of Neurobiology andNeurology, Founding Director of the JosephChief of the Division of Neurology, and Director of the Center for Human Genetics.clinical neurologists to apply molecular genetic strategies to neurological diseases. His lthe chromosomal location for more than 15 diseases, including several muscular dystrophies and LouGehrig’s disease. He led the team that in 1992 identified APOE as a major, widely confirmed susceptibility

onset Alzheimer’s disease. Translation of these findings to metabolicanalyses and drug discovery and development continued in GSK.

Dr. Roses was a member of the Science Board of the US Food and Drug Administration between 20032007. He was a member of the Board’s Subcommittee on Science and Technology that in 2007 authoredthe report “FDA Science and Mission at Risk.” He continues to consult with the FDA and other regulatoryagencies in the field of pharmacogenetics and companion diagnostics.

c Biomarker: Accelerating Drug Development for Alzheimer’s Disease andFrontotemporal Dementia

, Durham, NC

TOMM40 is the name for the gene adjacent to APOE on chromosome 19 in LD, contains manypolymorphic markers within its sequence [including introns]. A highly polymorphic polyT repeat variant[rs10524523] that is linked on the same strand to an APOE genotype variant. Our published work hasdescribed the relationship to the age of onset of symptoms leading to AD betweenvariant on each DNA stand and the APOE variant. We have constructed an algorithm based on TOMM40523 genotypes, APOE genotypes and age that will be tested in combination as a “prognostic biomarker” forthe design of a delay of onset of symptsubjects, as defined by neuropsychological testing. In Alliance with Takeda Pharmaceuticals, we plan toevaluate the effect of pioglitazone in delaying the onset of cognitive impairment o

523 is not a diagnostic test, or biomarker, for the diagnosis of AD until prospective PPV and NPVcan be assessed. This will be done concurrently with the delay of onset trial. The pharmacogenetic

risk population will use the 523 and APOE, with age of incident onset, as a prognosticpharmacogenetic biomarker. We have some additional data that may also support the involvement ofTOMM40 in Frontotemporal Dementia as well.

, FRCP (hon.), Duke Univers


management services to pharmaceutical and biotechnology companies, clinicalresearch and managed-healthcare organizations, and academicformed a team of consultants with deep experience in the practical application of PGx to

Dr. Roses also serves in several capacities at Duke University: asPilot Professor of Neurobiology and Genetics, as D

Discovery Institute, and as Senior Scholar at the Fuqua School of Business.long career as a Senior Vice President at GlaxoSmithKline (GSK) and its corporate

W). Upon joining GW in 1997, he organized genetic strategies forgene discovery, pharmacogenetics strategy and implementation, and integration of genetics

into medicine discovery and development. Subsequently at GSK, he headed research in clgenomics, proteomics, pharmacogenetics, and bioinformatics in support of the entire R&D pipeline.

During his previous tenure at Duke, Dr. Roses was Jefferson Pilot Professor of Neurobiology andNeurology, Founding Director of the Joseph and Kathleen Bryan Alzheimer’s Disease Research Center,Chief of the Division of Neurology, and Director of the Center for Human Genetics.clinical neurologists to apply molecular genetic strategies to neurological diseases. His lthe chromosomal location for more than 15 diseases, including several muscular dystrophies and LouGehrig’s disease. He led the team that in 1992 identified APOE as a major, widely confirmed susceptibility

imer’s disease. Translation of these findings to metabolicanalyses and drug discovery and development continued in GSK.

Dr. Roses was a member of the Science Board of the US Food and Drug Administration between 2003oard’s Subcommittee on Science and Technology that in 2007 authored

the report “FDA Science and Mission at Risk.” He continues to consult with the FDA and other regulatoryagencies in the field of pharmacogenetics and companion diagnostics.

Accelerating Drug Development for Alzheimer’s Disease and

TOMM40 is the name for the gene adjacent to APOE on chromosome 19 in LD, contains manyits sequence [including introns]. A highly polymorphic polyT repeat variant

[rs10524523] that is linked on the same strand to an APOE genotype variant. Our published work hasdescribed the relationship to the age of onset of symptoms leading to AD betweenvariant on each DNA stand and the APOE variant. We have constructed an algorithm based on TOMM40523 genotypes, APOE genotypes and age that will be tested in combination as a “prognostic biomarker” forthe design of a delay of onset of symptoms clinical trial in geographically collected populations of normalsubjects, as defined by neuropsychological testing. In Alliance with Takeda Pharmaceuticals, we plan toevaluate the effect of pioglitazone in delaying the onset of cognitive impairment o


pulation will use the 523 and APOE, with age of incident onset, as a prognosticpharmacogenetic biomarker. We have some additional data that may also support the involvement ofTOMM40 in Frontotemporal Dementia as well.

Duke Univers


management services to pharmaceutical and biotechnology companies, clinicalhealthcare organizations, and academic

formed a team of consultants with deep experience in the practical application of PGx toDr. Roses also serves in several capacities at Duke University: as

Pilot Professor of Neurobiology and Genetics, as DDiscovery Institute, and as Senior Scholar at the Fuqua School of Business.

long career as a Senior Vice President at GlaxoSmithKline (GSK) and its corporateW). Upon joining GW in 1997, he organized genetic strategies for

gene discovery, pharmacogenetics strategy and implementation, and integration of geneticsinto medicine discovery and development. Subsequently at GSK, he headed research in clgenomics, proteomics, pharmacogenetics, and bioinformatics in support of the entire R&D pipeline.

During his previous tenure at Duke, Dr. Roses was Jefferson Pilot Professor of Neurobiology andand Kathleen Bryan Alzheimer’s Disease Research Center,

Chief of the Division of Neurology, and Director of the Center for Human Genetics.clinical neurologists to apply molecular genetic strategies to neurological diseases. His lthe chromosomal location for more than 15 diseases, including several muscular dystrophies and LouGehrig’s disease. He led the team that in 1992 identified APOE as a major, widely confirmed susceptibility






[rs10524523] that is linked on the same strand to an APOE genotype variant. Our published work hasdescribed the relationship to the age of onset of symptoms leading to AD betweenvariant on each DNA stand and the APOE variant. We have constructed an algorithm based on TOMM40523 genotypes, APOE genotypes and age that will be tested in combination as a “prognostic biomarker” for

oms clinical trial in geographically collected populations of normalsubjects, as defined by neuropsychological testing. In Alliance with Takeda Pharmaceuticals, we plan toevaluate the effect of pioglitazone in delaying the onset of cognitive impairment o


pulation will use the 523 and APOE, with age of incident onset, as a prognosticpharmacogenetic biomarker. We have some additional data that may also support the involvement of

Duke University




Pilot Professor of Neurobiology and Genetics, as DDiscovery Institute, and as Senior Scholar at the Fuqua School of Business.














Allen D. Roses has established an international reputation for his work inpharmacogenetics, exploratory drug discovery, and clinical neuroscience.founded Cabernet Pharmaceuticals in 2008 to provide pharmacogenetics (PGx) and



Pilot Professor of Neurobiology and Genetics, as Director of the Deane DrugDiscovery Institute, and as Senior Scholar at the Fuqua School of Business. He recently returned to Duke





imer’s disease. Translation of these findings to metabolic


the report “FDA Science and Mission at Risk.” He continues to consult with the FDA and other regulatory







Allen D. Roses has established an international reputation for his work inclinical neuroscience.

founded Cabernet Pharmaceuticals in 2008 to provide pharmacogenetics (PGx) andmanagement services to pharmaceutical and biotechnology companies, clinical

healthcare organizations, and academic institutions. He hasformed a team of consultants with deep experience in the practical application of PGx to

Dr. Roses also serves in several capacities at Duke University: asirector of the Deane Drug

He recently returned to Dukelong career as a Senior Vice President at GlaxoSmithKline (GSK) and its corporate


into medicine discovery and development. Subsequently at GSK, he headed research in clinical genetics,genomics, proteomics, pharmacogenetics, and bioinformatics in support of the entire R&D pipeline.


Chief of the Division of Neurology, and Director of the Center for Human Genetics. He was one of the firstclinical neurologists to apply molecular genetic strategies to neurological diseases. His laboratory reportedthe chromosomal location for more than 15 diseases, including several muscular dystrophies and LouGehrig’s disease. He led the team that in 1992 identified APOE as a major, widely confirmed susceptibility

imer’s disease. Translation of these findings to metabolic





[rs10524523] that is linked on the same strand to an APOE genotype variant. Our published work hasdescribed the relationship to the age of onset of symptoms leading to AD between the TOMM40variant on each DNA stand and the APOE variant. We have constructed an algorithm based on TOMM40523 genotypes, APOE genotypes and age that will be tested in combination as a “prognostic biomarker” for

oms clinical trial in geographically collected populations of normalsubjects, as defined by neuropsychological testing. In Alliance with Takeda Pharmaceuticals, we plan toevaluate the effect of pioglitazone in delaying the onset of cognitive impairment of the Alzheimer’s type.



Allen D. Roses has established an international reputation for his work inDr. Roses

founded Cabernet Pharmaceuticals in 2008 to provide pharmacogenetics (PGx) andmanagement services to pharmaceutical and biotechnology companies, clinical-

institutions. He hasformed a team of consultants with deep experience in the practical application of PGx to




inical genetics,genomics, proteomics, pharmacogenetics, and bioinformatics in support of the entire R&D pipeline.


He was one of the firstaboratory reported

the chromosomal location for more than 15 diseases, including several muscular dystrophies and LouGehrig’s disease. He led the team that in 1992 identified APOE as a major, widely confirmed susceptibility

imer’s disease. Translation of these findings to metabolic-pathway

Dr. Roses was a member of the Science Board of the US Food and Drug Administration between 2003-oard’s Subcommittee on Science and Technology that in 2007 authored




[rs10524523] that is linked on the same strand to an APOE genotype variant. Our published work hasthe TOMM40-523

variant on each DNA stand and the APOE variant. We have constructed an algorithm based on TOMM40-523 genotypes, APOE genotypes and age that will be tested in combination as a “prognostic biomarker” for

oms clinical trial in geographically collected populations of normalsubjects, as defined by neuropsychological testing. In Alliance with Takeda Pharmaceuticals, we plan to

f the Alzheimer’s type.523 is not a diagnostic test, or biomarker, for the diagnosis of AD until prospective PPV and NPV

can be assessed. This will be done concurrently with the delay of onset trial. The pharmacogeneticpulation will use the 523 and APOE, with age of incident onset, as a prognostic

pharmacogenetic biomarker. We have some additional data that may also support the involvement of

Allen D. Roses has established an international reputation for his work inDr. Roses

founded Cabernet Pharmaceuticals in 2008 to provide pharmacogenetics (PGx) and

institutions. He hasformed a team of consultants with deep experience in the practical application of PGx to




inical genetics,


He was one of the firstaboratory reported

the chromosomal location for more than 15 diseases, including several muscular dystrophies and LouGehrig’s disease. He led the team that in 1992 identified APOE as a major, widely confirmed susceptibility

pathway

oard’s Subcommittee on Science and Technology that in 2007 authoredthe report “FDA Science and Mission at Risk.” He continues to consult with the FDA and other regulatory


[rs10524523] that is linked on the same strand to an APOE genotype variant. Our published work has523

523 genotypes, APOE genotypes and age that will be tested in combination as a “prognostic biomarker” foroms clinical trial in geographically collected populations of normal

subjects, as defined by neuropsychological testing. In Alliance with Takeda Pharmaceuticals, we plan tof the Alzheimer’s type.




William Hu

CSF Bioma

William Hu

Emory University School of Medicine

It is challenging clinically to distinguish between different pathologic subtypes of frontotemporal lobardegeneration (FTLD). Recently, using cases withproteomics a panel of analytes that could distinguish between FTLD with TDPTDP) and FTLD with tau pathology (FTLDrelated peptide arandom forest analysis achieved high sensitivity for FTLDTo validate these findings, we are recruiting 115 subjects from three acadin FTLD to undergo research CSF collection. Using a larger cohort of FTLD patients with knownpathology, we will determine the sensitivity and specificity of this novel panel to distinguish betweenFTLDfor CSF FTLD biomarkers.


William Hu

CSF Biomarkers of FTLD

William Hu


It is challenging clinically to distinguish between different pathologic subtypes of frontotemporal lobardegeneration (FTLD). Recently, using cases withproteomics a panel of analytes that could distinguish between FTLD with TDPTDP) and FTLD with tau pathology (FTLDrelated peptide arandom forest analysis achieved high sensitivity for FTLDTo validate these findings, we are recruiting 115 subjects from three acadin FTLD to undergo research CSF collection. Using a larger cohort of FTLD patients with knownpathology, we will determine the sensitivity and specificity of this novel panel to distinguish betweenFTLD-TDP and FTLDfor CSF FTLD biomarkers.


William Hu, MD, PhD,

Dr. Hu is an assistant professor of neurology at the Emory University School of Medicine.He obtained his medical and graduate training at the Mayo Clinic, and posttraining at the University of Pennsylvania.

His current research interests focus on developing and refining multineurodegenerative disorders including Alzheimer’s disease, frontotemporal lobardegenerations, and amyotrophic lateral sclerosis.

rkers of FTLD


It is challenging clinically to distinguish between different pathologic subtypes of frontotemporal lobardegeneration (FTLD). Recently, using cases withproteomics a panel of analytes that could distinguish between FTLD with TDPTDP) and FTLD with tau pathology (FTLDrelated peptide and adrenocorticotropic hormone), and chemokines (ILrandom forest analysis achieved high sensitivity for FTLDTo validate these findings, we are recruiting 115 subjects from three acadin FTLD to undergo research CSF collection. Using a larger cohort of FTLD patients with knownpathology, we will determine the sensitivity and specificity of this novel panel to distinguish between

TDP and FTLD-Tau. Thisfor CSF FTLD biomarkers.


PhD, Emory Univers



rkers of FTLD-TDP and

Emory University School of Medicine,

It is challenging clinically to distinguish between different pathologic subtypes of frontotemporal lobardegeneration (FTLD). Recently, using cases withproteomics a panel of analytes that could distinguish between FTLD with TDPTDP) and FTLD with tau pathology (FTLD

nd adrenocorticotropic hormone), and chemokines (ILrandom forest analysis achieved high sensitivity for FTLDTo validate these findings, we are recruiting 115 subjects from three acadin FTLD to undergo research CSF collection. Using a larger cohort of FTLD patients with knownpathology, we will determine the sensitivity and specificity of this novel panel to distinguish between

Tau. This presentation will give an update on the multifor CSF FTLD biomarkers.




FTLD-Tau:

, Decatur, GA

It is challenging clinically to distinguish between different pathologic subtypes of frontotemporal lobardegeneration (FTLD). Recently, using cases withproteomics a panel of analytes that could distinguish between FTLD with TDPTDP) and FTLD with tau pathology (FTLD-tau). These analytes include Fas, neuropeptides (agouti

nd adrenocorticotropic hormone), and chemokines (ILrandom forest analysis achieved high sensitivity for FTLDTo validate these findings, we are recruiting 115 subjects from three acadin FTLD to undergo research CSF collection. Using a larger cohort of FTLD patients with knownpathology, we will determine the sensitivity and specificity of this novel panel to distinguish between

presentation will give an update on the multi

ity School of Medicine



A Multi-Center Study

Decatur, GA

It is challenging clinically to distinguish between different pathologic subtypes of frontotemporal lobardegeneration (FTLD). Recently, using cases with known pathology, we identified through targetedproteomics a panel of analytes that could distinguish between FTLD with TDP

tau). These analytes include Fas, neuropeptides (agoutind adrenocorticotropic hormone), and chemokines (IL

random forest analysis achieved high sensitivity for FTLDTo validate these findings, we are recruiting 115 subjects from three acadin FTLD to undergo research CSF collection. Using a larger cohort of FTLD patients with knownpathology, we will determine the sensitivity and specificity of this novel panel to distinguish between



Dr. Hu is an assistant professor of neurology at the Emory University School of Medicine.He obtained his medical and graduate training at the Mayo Clinic, and post


Center Study

It is challenging clinically to distinguish between different pathologic subtypes of frontotemporal lobarknown pathology, we identified through targeted

proteomics a panel of analytes that could distinguish between FTLD with TDPtau). These analytes include Fas, neuropeptides (agouti

nd adrenocorticotropic hormone), and chemokines (ILrandom forest analysis achieved high sensitivity for FTLD-TDP (86%) with modest specificity (78%).To validate these findings, we are recruiting 115 subjects from three acadin FTLD to undergo research CSF collection. Using a larger cohort of FTLD patients with knownpathology, we will determine the sensitivity and specificity of this novel panel to distinguish between




His current research interests focus on developing and refining multineurodegenerative disorders including Alzheimer’s disease, frontotemporal lobar


proteomics a panel of analytes that could distinguish between FTLD with TDPtau). These analytes include Fas, neuropeptides (agouti

nd adrenocorticotropic hormone), and chemokines (IL-23, ILTDP (86%) with modest specificity (78%).

To validate these findings, we are recruiting 115 subjects from three academic centers with expertisein FTLD to undergo research CSF collection. Using a larger cohort of FTLD patients with knownpathology, we will determine the sensitivity and specificity of this novel panel to distinguish between

presentation will give an update on the multi-center validation study


His current research interests focus on developing and refining multi-modal biomarkers forneurodegenerative disorders including Alzheimer’s disease, frontotemporal lobar


proteomics a panel of analytes that could distinguish between FTLD with TDP-43 pathology (FTLDtau). These analytes include Fas, neuropeptides (agouti

23, IL-17). Classification byTDP (86%) with modest specificity (78%).

emic centers with expertisein FTLD to undergo research CSF collection. Using a larger cohort of FTLD patients with knownpathology, we will determine the sensitivity and specificity of this novel panel to distinguish between

center validation study

47

Dr. Hu is an assistant professor of neurology at the Emory University School of Medicine.He obtained his medical and graduate training at the Mayo Clinic, and post-doctoral

modal biomarkers forneurodegenerative disorders including Alzheimer’s disease, frontotemporal lobar


43 pathology (FTLD-tau). These analytes include Fas, neuropeptides (agouti -

17). Classification byTDP (86%) with modest specificity (78%).



Dr. Hu is an assistant professor of neurology at the Emory University School of Medicine.


17). Classification byTDP (86%) with modest specificity (78%).



48

Judith SiuciakInstitutes of Health

Pharmaceuticals, in Tarrytown, NY, where her laboratory focused on the neurochemical and behavioraleffects of neurotrophic factors, and their role in depression and neurodegenerative diseases. Dr. Siuciakreceived herinventor on two patents and has authored over 40 scientific publications in the field of Neuroscience andCNS drug discovery.

Use of Targeted Multiplex Proteomic StraBiomarkers in Alzheimer’s Disease

Judith Siuciak

Foundation for the National Institutes of Health, Inc.

The Foundation for the National Institutes of Health (FNIH) is the sole entity authorized by the U.S.Congress to raise private funds in support of NIH’s mission of improving health through scientific discoveryand translational research. Since 1996, FNIHincluding the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and The Biomarkers Consortium (BC).The mission of the BC is to strengthen the evidence for using new and existing biomarkers to improvdiagnosis, measure disease progression, guide treatment, accelerate drug development and targettherapies to individuals in several therapeutic areas, including neuroscience. The BC includes broadparticipation from government, industry, academia and patsector organizations.

The presentation will focus on two Biomarker Consortium projects which utilize Plasma and CSF samplesfrom ADNI, respectively. These studies will compare samples from healthy controAlzheimer’s Disease or Mild Cognitive Impairment. In addition, comparisons will be made in MCI subjectswho have progressed to dementia during the follow up period versus patients that had not progressed atthe time of analysis.

Judith SiuciakInstitutes of Health

Dr. Judy Siuciak, Scientific Program Manager at The Biomarkers Consortium, manages theactivities and projects of the Neuroscience Steering Committee. Prior to joining TheBiomarkers Consortium, Dr. Siuciak spent 17 years working in industry where she direvivo pharmacology laboratories engaged in CNS drug discovery research. While at Pfizer andBristolcognitive dysfunction and depression. Dr. Siuciak’s early caree

Pharmaceuticals, in Tarrytown, NY, where her laboratory focused on the neurochemical and behavioraleffects of neurotrophic factors, and their role in depression and neurodegenerative diseases. Dr. Siuciakreceived herinventor on two patents and has authored over 40 scientific publications in the field of Neuroscience andCNS drug discovery.


Judith Siuciak




Judith Siuciak, PhDInstitutes of Health

Dr. Judy Siuciak, Scientific Program Manager at The Biomarkers Consortium, manages theactivities and projects of the Neuroscience Steering Committee. Prior to joining TheBiomarkers Consortium, Dr. Siuciak spent 17 years working in industry where she direvivo pharmacology laboratories engaged in CNS drug discovery research. While at Pfizer andBristol-Myers Squibb, her laboratory focused on developing novel therapies for schizophrenia,cognitive dysfunction and depression. Dr. Siuciak’s early caree

Pharmaceuticals, in Tarrytown, NY, where her laboratory focused on the neurochemical and behavioraleffects of neurotrophic factors, and their role in depression and neurodegenerative diseases. Dr. Siuciakreceived her PhD in Neuropharmacology from the University of Illinois, College of Medicine. She is a coinventor on two patents and has authored over 40 scientific publications in the field of Neuroscience andCNS drug discovery.


Judith Siuciak




, PhD, The Biomarkers Consortium,

Dr. Judy Siuciak, Scientific Program Manager at The Biomarkers Consortium, manages theactivities and projects of the Neuroscience Steering Committee. Prior to joining TheBiomarkers Consortium, Dr. Siuciak spent 17 years working in industry where she direvivo pharmacology laboratories engaged in CNS drug discovery research. While at Pfizer and

Myers Squibb, her laboratory focused on developing novel therapies for schizophrenia,cognitive dysfunction and depression. Dr. Siuciak’s early caree

Pharmaceuticals, in Tarrytown, NY, where her laboratory focused on the neurochemical and behavioraleffects of neurotrophic factors, and their role in depression and neurodegenerative diseases. Dr. Siuciak

in Neuropharmacology from the University of Illinois, College of Medicine. She is a coinventor on two patents and has authored over 40 scientific publications in the field of Neuroscience and



The Foundation for the National Institutes of Health (FNIH) is the sole entity authorized by the U.S.Congress to raise private funds in support of NIH’s mission of improving health through scientific discoveryand translational research. Since 1996, FNIHincluding the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and The Biomarkers Consortium (BC).The mission of the BC is to strengthen the evidence for using new and existing biomarkers to improvdiagnosis, measure disease progression, guide treatment, accelerate drug development and targettherapies to individuals in several therapeutic areas, including neuroscience. The BC includes broadparticipation from government, industry, academia and pat

The presentation will focus on two Biomarker Consortium projects which utilize Plasma and CSF samplesfrom ADNI, respectively. These studies will compare samples from healthy controAlzheimer’s Disease or Mild Cognitive Impairment. In addition, comparisons will be made in MCI subjectswho have progressed to dementia during the follow up period versus patients that had not progressed at

The Biomarkers Consortium,





Use of Targeted Multiplex Proteomic Strategies to Identify Plasma and Cerebral Spinal FluidBiomarkers in Alzheimer’s Disease


The Foundation for the National Institutes of Health (FNIH) is the sole entity authorized by the U.S.Congress to raise private funds in support of NIH’s mission of improving health through scientific discoveryand translational research. Since 1996, FNIH has raised over $500 million towards over 100 projects,including the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and The Biomarkers Consortium (BC).The mission of the BC is to strengthen the evidence for using new and existing biomarkers to improvdiagnosis, measure disease progression, guide treatment, accelerate drug development and targettherapies to individuals in several therapeutic areas, including neuroscience. The BC includes broadparticipation from government, industry, academia and pat


The Biomarkers Consortium,





tegies to Identify Plasma and Cerebral Spinal Fluid

Foundation for the National Institutes of Health, Inc., Bethesda, MD

The Foundation for the National Institutes of Health (FNIH) is the sole entity authorized by the U.S.Congress to raise private funds in support of NIH’s mission of improving health through scientific discovery

has raised over $500 million towards over 100 projects,including the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and The Biomarkers Consortium (BC).The mission of the BC is to strengthen the evidence for using new and existing biomarkers to improvdiagnosis, measure disease progression, guide treatment, accelerate drug development and targettherapies to individuals in several therapeutic areas, including neuroscience. The BC includes broadparticipation from government, industry, academia and patient advocacy as well as other non


The Biomarkers Consortium, Foundation for the National






, Bethesda, MD


has raised over $500 million towards over 100 projects,including the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and The Biomarkers Consortium (BC).The mission of the BC is to strengthen the evidence for using new and existing biomarkers to improvdiagnosis, measure disease progression, guide treatment, accelerate drug development and targettherapies to individuals in several therapeutic areas, including neuroscience. The BC includes broad

ient advocacy as well as other non


Foundation for the National


Myers Squibb, her laboratory focused on developing novel therapies for schizophrenia,cognitive dysfunction and depression. Dr. Siuciak’s early career was spent at Regeneron






ient advocacy as well as other non




Myers Squibb, her laboratory focused on developing novel therapies for schizophrenia,r was spent at Regeneron






ient advocacy as well as other non-profit/private

The presentation will focus on two Biomarker Consortium projects which utilize Plasma and CSF samplesfrom ADNI, respectively. These studies will compare samples from healthy controls to patients withAlzheimer’s Disease or Mild Cognitive Impairment. In addition, comparisons will be made in MCI subjectswho have progressed to dementia during the follow up period versus patients that had not progressed at


Dr. Judy Siuciak, Scientific Program Manager at The Biomarkers Consortium, manages theactivities and projects of the Neuroscience Steering Committee. Prior to joining TheBiomarkers Consortium, Dr. Siuciak spent 17 years working in industry where she directed invivo pharmacology laboratories engaged in CNS drug discovery research. While at Pfizer and



in Neuropharmacology from the University of Illinois, College of Medicine. She is a co-inventor on two patents and has authored over 40 scientific publications in the field of Neuroscience and

tegies to Identify Plasma and Cerebral Spinal Fluid-Based


has raised over $500 million towards over 100 projects,including the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and The Biomarkers Consortium (BC).The mission of the BC is to strengthen the evidence for using new and existing biomarkers to improvediagnosis, measure disease progression, guide treatment, accelerate drug development and targettherapies to individuals in several therapeutic areas, including neuroscience. The BC includes broad

profit/private

The presentation will focus on two Biomarker Consortium projects which utilize Plasma and CSF samplesls to patients with

Alzheimer’s Disease or Mild Cognitive Impairment. In addition, comparisons will be made in MCI subjectswho have progressed to dementia during the follow up period versus patients that had not progressed at

Dr. Judy Siuciak, Scientific Program Manager at The Biomarkers Consortium, manages theactivities and projects of the Neuroscience Steering Committee. Prior to joining The

cted invivo pharmacology laboratories engaged in CNS drug discovery research. While at Pfizer and



inventor on two patents and has authored over 40 scientific publications in the field of Neuroscience and


has raised over $500 million towards over 100 projects,including the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and The Biomarkers Consortium (BC).

ediagnosis, measure disease progression, guide treatment, accelerate drug development and targettherapies to individuals in several therapeutic areas, including neuroscience. The BC includes broad

profit/private

The presentation will focus on two Biomarker Consortium projects which utilize Plasma and CSF samplesls to patients with

Alzheimer’s Disease or Mild Cognitive Impairment. In addition, comparisons will be made in MCI subjectswho have progressed to dementia during the follow up period versus patients that had not progressed at


Jos

Program Outcomthe coarticles on the relation of diet, diabetes, adiposity, insulin rwith cognitive disorders

Pilot Trial of Metformin in the Prevention of Alzheimer’s Disease

Jos

Columbia University

Type 2 diabetes and its related condition,disease in observational studies. Laboratory and experimental studies support a role of type 2 diabetes andhyperinsulinemia in brain deposition of amyloid, the putative culprit of Alzheimer’s dType 2 diabetes and hyperinsulinemia are known to cause cerebrovascular disease, another importantmechanism in Alzheimer’s disease. These facts have prompted the hypothesis that preventing type 2diabetes or decreasing hyperinsulinemiused for the treatment of Type 2 diabetes that is also effective and safe in its prevention. We hypothesizedthat metformin can decrease progression to dementia among overweight and obese persodiabetes with amnestic mild cognitive impairment. We have been conducting a phase 2 clinical trial ofmetformin in persons with amnestic mild cognitive impairment that includes clinical, imaging and biomarkeroutcomes. Recruitment of the2012 and we expect to report results in the Spring of 2012.


José A. Luchsinger

Program Outcomthe co-editor of the book “diabetes and the brain”, and has published several important peer reviewedarticles on the relation of diet, diabetes, adiposity, insulin rwith cognitive disorders


José A. Luchsinger

Columbia University



A. Luchsinger

José Alejandro Luchsinger is a general internist and epidemiologist. Dr. Luchsinger hasbeen working in risk factors for cognitive disorders including dementia and Alzheimer’sdisease since 1999. His focusmetabolic risk factors and diet with Alzheimer’s disease. He has been a coa large cohort study of aging in New York City, and a principal investigator of a cohortstudy of cogniticlinical trial of metformin, a medication for prevention of diabetes, in mild cognitiveimpairment. He leads the neurocognitive reading center of the Diabetes Prevention

Program Outcomes Study, and cognition ancillary study to the Finnish Diabetes Prevention Program. He iseditor of the book “diabetes and the brain”, and has published several important peer reviewed

articles on the relation of diet, diabetes, adiposity, insulin rwith cognitive disorders.


A. Luchsinger

Columbia University, New York, NY



A. Luchsinger, MD, MPH

José Alejandro Luchsinger is a general internist and epidemiologist. Dr. Luchsinger hasbeen working in risk factors for cognitive disorders including dementia and Alzheimer’sdisease since 1999. His focusmetabolic risk factors and diet with Alzheimer’s disease. He has been a coa large cohort study of aging in New York City, and a principal investigator of a cohortstudy of cognition in persons with diabetes. He is also the principal investigator of aclinical trial of metformin, a medication for prevention of diabetes, in mild cognitiveimpairment. He leads the neurocognitive reading center of the Diabetes Preventiones Study, and cognition ancillary study to the Finnish Diabetes Prevention Program. He is

editor of the book “diabetes and the brain”, and has published several important peer reviewedarticles on the relation of diet, diabetes, adiposity, insulin r


, New York, NY

Type 2 diabetes and its related condition,disease in observational studies. Laboratory and experimental studies support a role of type 2 diabetes andhyperinsulinemia in brain deposition of amyloid, the putative culprit of Alzheimer’s dType 2 diabetes and hyperinsulinemia are known to cause cerebrovascular disease, another importantmechanism in Alzheimer’s disease. These facts have prompted the hypothesis that preventing type 2diabetes or decreasing hyperinsulinemiused for the treatment of Type 2 diabetes that is also effective and safe in its prevention. We hypothesizedthat metformin can decrease progression to dementia among overweight and obese persodiabetes with amnestic mild cognitive impairment. We have been conducting a phase 2 clinical trial ofmetformin in persons with amnestic mild cognitive impairment that includes clinical, imaging and biomarkeroutcomes. Recruitment of the 80 participants of the trial is complete. The trial itself will finish in February of2012 and we expect to report results in the Spring of 2012.

, MPH, Columbia University

José Alejandro Luchsinger is a general internist and epidemiologist. Dr. Luchsinger hasbeen working in risk factors for cognitive disorders including dementia and Alzheimer’sdisease since 1999. His focus has been predominantly in the relationships of vascular andmetabolic risk factors and diet with Alzheimer’s disease. He has been a coa large cohort study of aging in New York City, and a principal investigator of a cohort

on in persons with diabetes. He is also the principal investigator of aclinical trial of metformin, a medication for prevention of diabetes, in mild cognitiveimpairment. He leads the neurocognitive reading center of the Diabetes Preventiones Study, and cognition ancillary study to the Finnish Diabetes Prevention Program. He is

editor of the book “diabetes and the brain”, and has published several important peer reviewedarticles on the relation of diet, diabetes, adiposity, insulin r


Type 2 diabetes and its related condition, hyperinsulinemia, are related to a higher risk of Alzheimer’sdisease in observational studies. Laboratory and experimental studies support a role of type 2 diabetes andhyperinsulinemia in brain deposition of amyloid, the putative culprit of Alzheimer’s dType 2 diabetes and hyperinsulinemia are known to cause cerebrovascular disease, another importantmechanism in Alzheimer’s disease. These facts have prompted the hypothesis that preventing type 2diabetes or decreasing hyperinsulinemia could prevent Alzheimer’s disease. Metformin is a medicationused for the treatment of Type 2 diabetes that is also effective and safe in its prevention. We hypothesizedthat metformin can decrease progression to dementia among overweight and obese persodiabetes with amnestic mild cognitive impairment. We have been conducting a phase 2 clinical trial ofmetformin in persons with amnestic mild cognitive impairment that includes clinical, imaging and biomarker

80 participants of the trial is complete. The trial itself will finish in February of2012 and we expect to report results in the Spring of 2012.

Columbia University

José Alejandro Luchsinger is a general internist and epidemiologist. Dr. Luchsinger hasbeen working in risk factors for cognitive disorders including dementia and Alzheimer’s

has been predominantly in the relationships of vascular andmetabolic risk factors and diet with Alzheimer’s disease. He has been a coa large cohort study of aging in New York City, and a principal investigator of a cohort


editor of the book “diabetes and the brain”, and has published several important peer reviewedarticles on the relation of diet, diabetes, adiposity, insulin resistance, and vascular risk factors in general


hyperinsulinemia, are related to a higher risk of Alzheimer’sdisease in observational studies. Laboratory and experimental studies support a role of type 2 diabetes andhyperinsulinemia in brain deposition of amyloid, the putative culprit of Alzheimer’s dType 2 diabetes and hyperinsulinemia are known to cause cerebrovascular disease, another importantmechanism in Alzheimer’s disease. These facts have prompted the hypothesis that preventing type 2

a could prevent Alzheimer’s disease. Metformin is a medicationused for the treatment of Type 2 diabetes that is also effective and safe in its prevention. We hypothesizedthat metformin can decrease progression to dementia among overweight and obese persodiabetes with amnestic mild cognitive impairment. We have been conducting a phase 2 clinical trial ofmetformin in persons with amnestic mild cognitive impairment that includes clinical, imaging and biomarker

80 participants of the trial is complete. The trial itself will finish in February of2012 and we expect to report results in the Spring of 2012.

Columbia University




editor of the book “diabetes and the brain”, and has published several important peer reviewedesistance, and vascular risk factors in general




80 participants of the trial is complete. The trial itself will finish in February of









has been predominantly in the relationships of vascular andmetabolic risk factors and diet with Alzheimer’s disease. He has been a co-investigator ina large cohort study of aging in New York City, and a principal investigator of a cohort



hyperinsulinemia, are related to a higher risk of Alzheimer’sdisease in observational studies. Laboratory and experimental studies support a role of type 2 diabetes andhyperinsulinemia in brain deposition of amyloid, the putative culprit of Alzheimer’s disease. In addition,Type 2 diabetes and hyperinsulinemia are known to cause cerebrovascular disease, another importantmechanism in Alzheimer’s disease. These facts have prompted the hypothesis that preventing type 2

a could prevent Alzheimer’s disease. Metformin is a medicationused for the treatment of Type 2 diabetes that is also effective and safe in its prevention. We hypothesizedthat metformin can decrease progression to dementia among overweight and obese persons without type 2diabetes with amnestic mild cognitive impairment. We have been conducting a phase 2 clinical trial ofmetformin in persons with amnestic mild cognitive impairment that includes clinical, imaging and biomarker


49


has been predominantly in the relationships of vascular andinvestigator in

a large cohort study of aging in New York City, and a principal investigator of a cohorton in persons with diabetes. He is also the principal investigator of a

clinical trial of metformin, a medication for prevention of diabetes, in mild cognitiveimpairment. He leads the neurocognitive reading center of the Diabetes Preventiones Study, and cognition ancillary study to the Finnish Diabetes Prevention Program. He is


hyperinsulinemia, are related to a higher risk of Alzheimer’sdisease in observational studies. Laboratory and experimental studies support a role of type 2 diabetes and

isease. In addition,Type 2 diabetes and hyperinsulinemia are known to cause cerebrovascular disease, another importantmechanism in Alzheimer’s disease. These facts have prompted the hypothesis that preventing type 2

a could prevent Alzheimer’s disease. Metformin is a medicationused for the treatment of Type 2 diabetes that is also effective and safe in its prevention. We hypothesized

ns without type 2diabetes with amnestic mild cognitive impairment. We have been conducting a phase 2 clinical trial ofmetformin in persons with amnestic mild cognitive impairment that includes clinical, imaging and biomarker



has been predominantly in the relationships of vascular andinvestigator in

a large cohort study of aging in New York City, and a principal investigator of a cohorton in persons with diabetes. He is also the principal investigator of a

clinical trial of metformin, a medication for prevention of diabetes, in mild cognitiveimpairment. He leads the neurocognitive reading center of the Diabetes Preventiones Study, and cognition ancillary study to the Finnish Diabetes Prevention Program. He is


hyperinsulinemia, are related to a higher risk of Alzheimer’sdisease in observational studies. Laboratory and experimental studies support a role of type 2 diabetes and

isease. In addition,Type 2 diabetes and hyperinsulinemia are known to cause cerebrovascular disease, another importantmechanism in Alzheimer’s disease. These facts have prompted the hypothesis that preventing type 2

a could prevent Alzheimer’s disease. Metformin is a medicationused for the treatment of Type 2 diabetes that is also effective and safe in its prevention. We hypothesized

ns without type 2diabetes with amnestic mild cognitive impairment. We have been conducting a phase 2 clinical trial ofmetformin in persons with amnestic mild cognitive impairment that includes clinical, imaging and biomarker


50

NOTES


NOTES

Documents

12TH INTERNATIONAL CONFERENCE ON ALZHEIMER’S DRUG … · The Alzheimer’s Drug Discovery Foundation organizes two annual international scientific conferences as ... The Discovery