The Relationship between Blood and CNS levels of Beta Amyloid and Alzheimer’s DiseaseGloria Tong (glo.tong@mail.utoronto.ca)

Shakira Hakimzadah (s.hakimzadah@mail.utoronto.ca)

Meiko Peng(meiko.peng@mail.utoronto.ca)

Hanae Mohamed (hanae.mohamed@mail.utoronto.ca)

PHM142 Fall 2014Coordinator: Dr. Jeffrey HendersonInstructor: Dr. David Hampson

What is Alzheimer’s Disease?

• Alzheimer's Disease (AD) is the most common form of dementia prevalent in the elderly (Avg. age at 65+)1

• AD becomes more serious over time and presently has no cure1

• 1 in 11 Canadians over 65 has AD or related dementia2

• Symptoms include memory loss, disorientation, mood swings, poor judgment, inability to speak or walk properly1

Pathogenesis of AD

• Plaque formation Accumulation of Beta Amyloid (Aβ) in the brain to form deposits1

• Tangle formation Build up of hyperphosphorylated Tau protein in the brain to form twisted fibres3

• Processes occur naturally with age, but develops more rapidly Alzheimer’s patients1

Harmful effects of plaques:• Interfere with synapses4

• Increase in cofilin which is an enzyme that breaks down actin (component of synapse)4

• Oxidative damage5

• Many other theories4

6

What is Beta Amyloid?

• Beta amyloid (Aβ) is a protein derived from amyloid precursor protein (APP)7

• At normal levels, Aβ is necessary for synaptic plasticity and neuronal survival8

• Overproduction and reduced clearance of Aβ forms insoluble aggregates in the brain, which affects neuronal function9

10

APP Processing

• Amyloid precursor protein (APP) is a transmembrane protein whose primary functions include nuclear signalling, communication between cells, and cell growth and development7

• APP is first cleaved by the β-secretase7

• Subsequent cleavage by γ-secretase releases Aβ7

• With accumulation, Aβ aggregates with other Aβ proteins to form plaques in the brain1

12

AD Treatments

• No cure currently• Aim to lessen symptoms and improve quality of life

• Therapeutic intervention depends on proposed pathogenic mechanism

11

Secretase Inhibitors

• Inhibit β- or γ-secretase enzymes to prevent production of Aβ from APP13

• Increased cognition in animal models• β-secretase inhibitors: rosiglitazone, pioglitazone13

• Stimulate the nuclear peroxisome proliferator-activated receptor γ (PPAR- γ)

• Suppress β-secretase expression; promote APP degradation• γ-secretase inhibitors: semagacestat, begacestat13

• Reduce Aβ concentrations in plasma and production in the CNS9

Blood-Brain Barrier

• Highly selective permeable barrier composed of capillary endothelial cells cemented by tight junctions14

• Transcellular transport14

• Allows for supply of nutrients, while protecting the brain from harmful toxins14

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Modulation of Aβ Transport and the Blood-Brain Barrier • Influx into brain: RAGE16

• Clearance out of brain: LRP116

• AD patients have increased RAGE expression and decreased LRP expression17

• Aβ accumulation in brain; neurotoxic activation

Compound PF04494700 blocks RAGE/ β-amyloid interaction - Phase 2 Clinical Trials

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Future Research Directions

Target Aβ clumps in the brain via:11• Vaccination18

• DNA encoding Aβ is injected to activate immune response

• IV infusions of anti-amyloid antibodies (blood donations)19

• IVIg binds to fibrillar and oligomeric Aβ amyloid

• Intravenous Immune Globulin (IVIg) contains antibodies, currently in Phase 3

The Prizes

1 - $100

2 - $200

3 - $500

$100

What transmembrane protein is beta-amyloid derived from?

B - BPS

A - APS

C - CNS

D - APPD - APP

$200

Which is not an effect of beta amyloid plaques in the brain?

B – Increase in Cofilin enzyme

A – Interference with synapse

C – Oxidative damage

D – Kidney failureD – Kidney Failure

$500

How do secretase inhibitors work?

B – inhibit release of epinephrineA – stimulate PPAR-γ receptors, no APP expressed

C – destroy brain cells

D – interfere with estrogen levels

A – stimulate PPAR-γ receptors

Summary• APP is a transmembrane protein that is responsible for many cellular functions, including cell communication, cell

growth, and development.

• APP is cleaved by β-secretase to produce sAPPB, and cleaved a second time by γ-secretase to form Aβ protein

• The cause of Alzheimer's Disease (AD) is due to the accumulation of beta amyloid proteins in the brain to form plaques, which interferes with neurotransmitter transduction between synapses.

• Currently no cure for AD, therapeutic interventions aim to lesson symptoms and slow down disease progression

• Treatments:

• Reduce production of beta amyloid proteins by targeting beta and gamma secretase inhibitors• β-secretase inhibitors: rosiglitazone, pioglitazone• Υ-secretase inhibitors: semagacestat, begacestat

• Reduce influx across blood-brain barrier• Target RAGE, a transporter responsible for beta amyloid influx into the BBB• Drug is currently in Phase 2 clinical

• Increase clearance out of the BBB• Activate LRP1, a transporter responsible for Aβ efflux• Currently no clinical drugs available

• Vaccinations and using blood transfusions are treatment methods that are currently being explored to treat AD

References1. Alzeimer’s Association. C2014. [Internet]. Alzeimer’s Association. Chicago (US). What Is Alzheimer's. Available from: http://www.alz.org/

alzheimers_disease_what_is_alzheimers.asp

2. Rising Tide – The Impact of Dementia on Canadian Society. Alzheimer Society of Canada (Executive Summary - pdf, 24 pages; Full Report - pdf, 65 pages; Risk Analytica - pdf, 344 pages)

3. Eva-Maria Mandelkow, Eckhard Mandelkow, Tau in Alzheimer's disease, Trends in Cell Biology, Volume 8, Issue 11, 1 November 1998, Pages 425-427

4. Goldman, B. (2013, September 19). Scientists reveal how beta-amyloid may cause Alzheimer's. Retrieved October 10, 2014, from http://med.stanford.edu/news/all-news/2013/09/scientists-reveal-how-beta-amyloid-may-cause-alzheimers.html

5. O’Brien, R.J. and Wong P.C., Amyloid precursor protein processing and alzheimer’s disease. Annu. Rev. Neurosci. 34, 185–204 (2011).

6. Amyloid Plaques & Neurofibrillary Tangles. (2000, January 1). Retrieved October 11, 2014, from http://www.brightfocus.org/alzheimers/about/understanding/plaques-and-tangles.html

7. Priller C., Bauer T., Mitteregger G., Krebs B., Kretzschmar H.A., and Herms J. Synapse formation and function is modulated by the amyloid precursor protein. Jneurosci. 26(27), 7212-7221 (2006).

8. Parihar, M., & Brewery, G. (2010). Amyloid Beta as a Modulator of Synaptic Plasticity. J Alzheimers Dis., 22(3), 741-763.

9. Laferla, F. (2008). Amyloid-β and tau in Alzheimer's disease. Nature Reviews Neuroscience.

10. Wärmländer, S., & Timan, A. (2013). Biophysical Studies of the Amyloid β-Peptide: Interactions with Metal Ions and Small Molecules. ChemBioChem, 14(14), 1692-1704.

11. Mangialasche, F., Solomon, A., Winblad, B., Mecocci, P., Kivipelto, M. (2010) Alzheimer’s disease: clinical trials and drug development. The Lancet Neurology, 9, 702-716.

12. Amyloid-b Precursor Protein. (2006, January 1). Retrieved October 11, 2014, from http://www.ebi.ac.uk/interpro/potm/2006_7/Page2.htmS

13. Seeman, P., and Seeman, N. (2011) Alzheimer's disease: B-amyloid plaque formation in human brain. Synapse, 65(12), 1289-1297.

14. The Blood-Brain Barrier: Bottleneck in Brain Drug Development. Neuro Rx. Jan 2005. 2(1): 3-14.

15. Anderson, K. (2010, January 1). Bacterial Meningitis. Retrieved October 11, 2014, from http://bacterial-meningitis.weebly.com/physiology.html

16. Scarpini, E., Scheltens, P., and Feldman, H. (2003) Treatment of Alzheimer's disease: current status and new perspectives. The Lancet Neurology, 2(9), 539-547.

17. Deane, R., Bell, R.D., Sagare, A., and Zlokovic, B.V. (2009) Clearance of amyloid-beta peptide across the blood-brain barrier: implication for therapies in Alzheimer’s disease. CNS Neurol Disord Drug Targets, 8(1), 16-30.

18. Lambracht-Washington, D., and Rosenberg, R., (2013) Advances in the Development of Vaccines for Alzheimer’s Disease. Discovery Medicine 15(84):319-326

19. Intravenous Immune Globulin ((IVIG) Study, Alzheimer’s Disease Education & Referral Center, http://www.adcs.org/studies/igiv.aspx Retrieved on October 1st, 2014..