2

• Huntington’s disease

• Parkinson’s disease

• Amylotrophic lateral sclerosis

• Alzheimer’s Disease

Neurodegenerative Disorders

• Degenerative brain disorder developed in adulthood (brain cells die)

• Progressive and irreversible decline in memory and other cognitive abilities

• ~4.5 million people in America

Some Facts

• Forgetfulness and loss of smell

• Memory loss becomes more severe

• Language, perceptual, and motor skills deteriorate

• Mood becomes unstable

• Lost of mobility and control of body functions

• Death

Symptoms

http://www.alzheimers.org/rmedia/mediaroom.htm#animation

• Diagnosis by exclusion– Medical history and mental status exams– Physical examination– Neurological exam– Blood count– CT, PET, and MRI scans to detect brain

volume and activity

• Confirmed by autopsy• Tau and β-amyloid test?• Other developed tests have been

unsuccessful

Diagnosis

• Genetics– Apolipoprotein E4 (APOE4)– Deletions in gene coding for α-macroglobulin

(serum protease inhibitor)– LDL gene?

• Type II Diabetes• Down Syndrome• High cholesterol levels• Stroke and previous head injuries• Tobacco• High homocysteine concentration in blood

Risk Factors

• Familial Alzheimer’s Disease– Caused by a genetic mutation– All are early onset (younger than 60 years)– Accounts for 10% of the cases

• Sporadic Alzheimer’s Disease– Most common (90% of the cases)– Typically occurs after age 65

Types

• Older patients of Down’s syndrome also have neurofirillary tangles and senile plaques

Martin, Joseph, N Engl J Med

1

1

Familial Autosomal AD

• Amyloid hypothesis– β-amyloid protein

• tau hypothesis– tau protein

Hypotheses

http://www.alzheimers.org/rmedia/mediaroom.htm#animation

• Appear first in the cerebral cortex

• Results from improper cleavage of APP

• Made by β-amyloid, tau, ubiquitin, α-antichymotrypsin, apolipoprotein E, presenilins 1 and 2, α-macroglobulin

• β-amyloid fragment (39 – 43 a.a.) is “sticky” and aggregates

• Forms intracellularly and transported outside of the neuron

Senile Plaques

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12525689

• Activates de immune system

• Disrupts neuron communication and inflammation

• β-amyloid facilitates Ca+2 entry to neurons

• Mitogen-Activated Protein Kinase (MAPK)

• Inhibits ubiquitin degradation

• Insufficient to cause cell death

• High metal concentration

Senile Plaques

APP Copper binding domain

Senile Plaques

http://www.alzheimers.org/rmedia/mediaroom.htm#animation

Senile Plaques

http://www.alzheimers.org/rmedia/mediaroom.htm#animation

Senile Plaques

http://www.alzheimers.org/rmedia/mediaroom.htm#animation

Martin, Joseph, N Engl J Med

known mutations

Senile Plaques

Amyloid Tracer

• “Compound B” highlights β-amyloid

• Currently under human trials

• Developed at the University of Pittsburgh Sweden's Uppsala University

University of Pittsburgh Medical Center

S

N

OH

HN

2-(4'-methylaminophenyl)-6-hydroxy-benzothiazole

PIB

Proc Natl Acad Sci U S A. 2003 October 14; 100(21): 12462–12467.

Presenilin 1 mutations

Presenilin 2 mutations

Martin, Joseph, N Engl J Med

Presenilin

• Astrocytes become more numerous and produce prostaglandin mediated inflammation

• Microglial cells produce free radicals– Produce InterLeukin-1β (IL-1β) and Tumor

Necrosis-α (TNF-α) (inflammatory cytokines)– Induce enzymes like nitric oxide synthetase

• Inflammation damages neurons causing neuron death

Astrocytes and Microglia Cells

• Typically begin in the entorhinal cortex• Visualized as paired helical filaments on

electron microscopy • tau protein maintains the structural

integrity of microtubules within neurons• In AD, tau protein becomes

hyperphosporylated• Hyperphosporylated tau binds to each

other forming NFTs• Neurons full of NFTs die

Neurofibrillary Tangles

Neurofibrillary Tangles

http://www.alzheimers.org/rmedia/mediaroom.htm#animation

• NFTs not present in all cases

• NFTs kill output neurons mostly:– Cholinergic neurons (Ach)– Large pyramidal neurons– Output neurons in the hippocampus

Neurofibrillary Tangles

• Protein portion of lipoproteins (LDL, HDL, etc.) that transport cholesterol

• Synthesized in the liver, by the brain astrocytes, and oligodendrocytes

• Does not cross the Blood Brain Barrier

• Important risk factor

Apolipoprotein

• 299aa glycoprotein

• Acts as the binding site for LDL receptors– Allows lipids to get into the cell

• Major lipoprotein for lipid transport between neurons– cholesterol used for synapse plasticity and

repair of damaged neurons

• Removes oxidized lipids from the brain

• Three common forms (E2, E3, and E4)

• Usually secreted after brain damage

Apolipoprotein E

• High insulin concentration stimulates nitric oxide synthetase– Combines nitric oxide with superoxide to

produce peroxynitrite– Peroxynitrite causes Tyr nitration

• AD patients show high Tyr nitration in both neurons and glial cells

Insulin

• Nicotine in rats produces elevation of Nerve Growth Factor, enhancing Acetylcholine production and release

• Nicotine reduces β-amyloid production

• Incidence of AD is more than double for smokers compared to non-smokers

Tobacco

N

N

• Acetylcholinesterase inhibitors

• NMDA Receptor Antagonists– Memantine (Namenda)

• β-secretase (BACE) inhibitor?

• Anti-amyloid vaccine?

• Detoxification of β-amyloid?

• Metal ions reduction (Clioquinol)?

• Vitamin E intake

Treatments

• Regulate attention, the first stage of learning, and memory

• Use acetylcholine as a neurotransmitter

• Have more microtubules than other neurons

Cholinergic Neurons

• Breaks acetylcholine

• Promotes aggregation of β-amyloid

Acetylcholinesterase

O N+

O

acetylcholine

HO N+

cholineO

-O

acetate

++H2O O N+

O

O

tetrahedral intermediateH

H

Donepezil (Aricept)

Galantamine (Reminyl)

Rivastigmine (Exelon)

Tacrine (Cognex)

Acetylcholine

O N+

O

O

HH

HO

NH

CH3

OBr

N

NH2 H

Cl

H

O

H

N

O N

O

C4H6O6

O

H2C

N

CH2

O

CH3

O CH3

H

Cl

AchE Inhibitors

• Memantine/Auxura/Namenda• Regulates Calcium influx• Replaces Magnesium Ions

NMDA Receptor

Antagonist

• Chelates copper and zinc in vitro

• Treatment reversed the deposition of amyloid in the brains of mice with AD

• Clioquinol cut amyloid deposits in half over a nine week period with no adverse effects.

Clioquinol

N

OH

I

Cl