1. The Relationship between Blood and CNS levels of Beta Amyloid and Alzheimer’s Disease Gloria Tong (glo.tong@mail.utoronto.ca)glo.tong@mail.utoronto.ca Shakira Hakimzadah (s.hakimzadah@mail.utoronto.ca)s.hakimzadah@mail.utoronto.ca Meiko Peng(meiko.peng@mail.utoronto.ca)meiko.peng@mail.utoronto.ca Hanae Mohamed (hanae.mohamed@mail.utoronto.ca)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 cure 1 1 in 11 Canadians over 65 has AD or related dementia 2 Symptoms include memory loss, disorientation, mood swings, poor judgment, inability to speak or walk properly 1

3. Pathogenesis of AD Plaque formation  Accumulation of Beta Amyloid (A β ) in the brain to form deposits 1 Tangle formation  Build up of hyperphosphorylated Tau protein in the brain to form twisted fibres 3 Processes occur naturally with age, but develops more rapidly Alzheimer’s patients 1 Harmful effects of plaques: Interfere with synapses 4 Increase in cofilin which is an enzyme that breaks down actin (component of synapse) 4 Oxidative damage 5 Many other theories 4 6

4. What is Beta Amyloid? Beta amyloid (A β ) is a protein derived from amyloid precursor protein (APP) 7 At normal levels, A β is necessary for synaptic plasticity and neuronal survival 8 Overproduction and reduced clearance of A β forms insoluble aggregates in the brain, which affects neuronal function 9 10

5. APP Processing Amyloid precursor protein ( APP) is a transmembrane protein whose primary functions include nuclear signalling, communication between cells, and cell growth and development 7 APP is first cleaved by the β-secretase 7 Subsequent cleavage by γ-secretase releases A β 7 With accumulation, A β aggregates with other A β proteins to form plaques in the brain 1 12

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

7. Secretase Inhibitors Inhibit β- or γ-secretase enzymes to prevent production of A β from APP 13 Increased cognition in animal models β-secretase inhibitors: rosiglitazone, pioglitazone 13 Stimulate the nuclear peroxisome proliferator-activated receptor γ (PPAR- γ) Suppress β-secretase expression; promote APP degradation γ-secretase inhibitors: semagacestat, begacestat 13 Reduce A β concentrations in plasma and production in the CNS 9

8. Blood-Brain Barrier Highly selective permeable barrier composed of capillary endothelial cells cemented by tight junctions 14 Transcellular transport 14 Allows for supply of nutrients, while protecting the brain from harmful toxins 14 15

9. Modulation of A β Transport and the Blood-Brain Barrier Influx into brain: RAGE 16 Clearance out of brain: LRP1 16 AD patients have increased RAGE expression and decreased LRP expression 17 A β accumulation in brain; neurotoxic activation Compound PF04494700 blocks RAGE/ β-amyloid interaction - Phase 2 Clinical Trials 16

10. Future Research Directions Target A β clumps in the brain via:11 Vaccination 18 DNA encoding A β is injected to activate immune response IV infusions of anti-amyloid antibodies (blood donations) 19 IVIg binds to fibrillar and oligomeric A β amyloid 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? B - BPS A - APS C - CNS D - APP

14. $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

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

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 A β 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 A β efflux Currently no clinical drugs available Vaccinations and using blood transfusions are treatment methods that are currently being explored to treat AD

17. References 1.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 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 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 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.htmShttp://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.htmlhttp://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..http://www.adcs.org/studies/igiv.aspx