The Relationship between Blood and CNS levels of Beta Amyloid and Alzheimer’s Disease

1. The Relationship between Blood and CNS levels of Beta Amyloid and Alzheimer’s Disease Gloria Tong (glo.tong@mail.utoronto.ca) Shakira Hakimzadah (s.hakimzadah@mail.utoronto.ca) MeikoPeng(meiko.peng@mail.utoronto.ca) HanaeMohamed (hanae.mohamed@mail.utoronto.ca) PHM142 Fall 2014 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

2. 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

3. 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

4. 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

5. 12 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

6. 11 AD Treatments No cure currently Aim to lessen symptoms and improve quality of life Therapeutic intervention depends on proposed pathogenic mechanism

7. 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

8. 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 15

9. 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 16

10. Future Research Directions Target Aβ clumps in the brain via:11 • Vaccination18 • DNA encoding Aβis injected to activate immune response • IV infusions of anti-amyloid antibodies (blood donations)19 • IVIg binds to fibrillar and oligomeric Aβamyloid • Intravenous Immune Globulin (IVIg) contains antibodies, currently in Phase 3

12. The Prizes 1- $100 2- $200 3- $500

13. $100 What transmembrane protein is beta-amyloid derived from? A - APS B - BPS C - CNS D - APP D - APP

14. $200 Which is not an effect of beta amyloid plaques in the brain? A – Interference with synapse B – Increase in Cofilin enzyme C – Oxidative damage D – Kidney Failure D – Kidney failure

15. $500 How do secretase inhibitors work? A – stimulate PPAR-γreceptors A – stimulate PPAR-γreceptors, no APP expressed B – inhibit release of epinephrine C – destroy brain cells D – interfere with estrogen levels

16. 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

17. References • Alzeimer’sAssociation. C2014. [Internet]. Alzeimer’s Association. Chicago (US). What Is Alzheimer's. Available from: http://www.alz.org/alzheimers_disease_what_is_alzheimers.asp • 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) • Eva-Maria Mandelkow, EckhardMandelkow, Tau in Alzheimer's disease, Trends in Cell Biology, Volume 8, Issue 11, 1 November 1998, Pages 425-427 • 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 • O’Brien, R.J. and Wong P.C., Amyloid precursor protein processing and alzheimer’s disease. Annu. Rev. Neurosci. 34, 185–204 (2011). • Amyloid Plaques & Neurofibrillary Tangles. (2000, January 1). Retrieved October 11, 2014, from http://www.brightfocus.org/alzheimers/about/understanding/plaques-and-tangles.html • PrillerC., 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). • Parihar, M., & Brewery, G. (2010). Amyloid Beta as a Modulator of Synaptic Plasticity. J Alzheimers Dis.,22(3), 741-763. • Laferla, F. (2008). Amyloid-β and tau in Alzheimer's disease. Nature Reviews Neuroscience. • Wärmländer, S., & Timan, A. (2013). Biophysical Studies of the Amyloid β-Peptide: Interactions with Metal Ions and Small Molecules. ChemBioChem,14(14), 1692-1704. • 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. • Amyloid-b Precursor Protein. (2006, January 1). Retrieved October 11, 2014, from http://www.ebi.ac.uk/interpro/potm/2006_7/Page2.htmS • Seeman, P., and Seeman, N. (2011) Alzheimer's disease: B-amyloid plaque formation in human brain. Synapse, 65(12), 1289-1297. • The Blood-Brain Barrier: Bottleneck in Brain Drug Development. Neuro Rx. Jan 2005. 2(1): 3-14. • Anderson, K. (2010, January 1). Bacterial Meningitis. Retrieved October 11, 2014, from http://bacterial-meningitis.weebly.com/physiology.html • 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. • 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 NeurolDisord Drug Targets, 8(1), 16-30. • Lambracht-Washington, D., and Rosenberg, R., (2013) Advances in the Development of Vaccines for Alzheimer’s Disease. Discovery Medicine 15(84):319-326 • Intravenous Immune Globulin ((IVIG) Study, Alzheimer’s Disease Education & Referral Center, http://www.adcs.org/studies/igiv.aspx Retrieved on October 1st, 2014..