Alzheimer’s Disease: Research & Implications on Society

1. Alzheimer’s Disease:Research & Implications on Society By: Reshma Erukulla

2. Did Reagan Suffer from Alzheimer’s while in office?

3. This goes to show that anyone is susceptible to this disease. Most of us probably know someone who suffers from it currently, has suffered from it, or will know someone who will suffer from it.

4. Basic Statistics • 5.3 million suffer from Alzheimer’s Disease in USA alone (will increase due to Baby Boomers) • 172 billion dollars in costs annually • 10.9 million unpaid caregivers • 7thleading cause of death last year • 72,432deaths reported last year 2010 Alzheimer’s Disease Facts and Figures

5. Chances of having Alzheimer’s 2010 Alzheimer’s Disease Facts and Figures

6. Alzheimer’s Death Rates (per 100000) 2010 Alzheimer’s Disease Facts and Figures

7. Care Giving for Patients • By 2030 estimated 36000 geriatrics specialists will be needed. • The 10.9 million who provided unpaid healthcare put in a total of 12.5 billion hours, which totals to $144 billion. • Care giving has a negative impact 2010 Alzheimer’s Disease Facts and Figures

8. Health Care System & Alzheimer’s • Expected Payments for 2010 are estimated to be about $172 billion (including Medicaid & Medicare. ) • Direct effect on businesses who suffer from losses due to care givers occupied with an Alzheimer’s patient. • Average payment for an Alzheimer’s patient at the hospital is : $7663 2010 Alzheimer’s Disease Facts and Figures

9. Pharmaceutical Industry • Creation of new companies to target Alzheimer’s Disease specifically (Archer Pharmaceuticals, Inc.) • Some companies have specialized branches for Alzheimer’s (Elan Pharmaceuticals, Inc.) • In 2009 (as estimated in 2005) the Drug Industry for Alzheimer’s was supposed to hit $5.5 billion.

10. Alzheimer’s Disease & the Patient • There are seven stages to Alzheimer’s Disease, each one gradually becoming worse than the other • Affects the brain - Cognitive Impairment ; affects daily activities • Better to get diagnosed earlier as it increases the chances of lessening the impact of problems

11. Biochemistry Aspect of Alzheimer’s • Amyloid Precursor Protein - Transmembrane protein necessary to vital brain function (neuron growth, post-injury repair, etc), which is “cut” by enzymes, and then forms Abeta fibrils • Abeta Peptide - The peptide that make up the aggregated plaques outside of the cell inside the brain. • Beta secretase (gamma secretase) [BACE] - This is the enzyme that severs the APP forming the Abeta plaques. • Tau Protein - Caused by abnormal aggregation of tau protein, tau protein is part of cytoskeleton, when hyperphosphorylated, it creates tangles, and disrupts neuron’s transport system

12. Amyloid Precursor Protein (APP) Alpha Helix C Alternating Beta Sheets N

13. Breakdown of APP Beta Gamma KPI Ox2 GFD Acidic E2 Cyto CuBD Unstructured TM 123 18 189 289 498 524 648 695

14. Copper Binding Domain on APP His147 Note: 2 Water molecules present with a Copper ion. His151 Met170 Tyr168

15. APP in the form of a Dimer Asymmetric Unit of Heparin Induced E1-Dimer of APP.

16. Beta Amyloid N terminal seen in blue, whereas C-terminus is the red. C – terminus helix lost its conformational state first, whereas the N – terminal stayed stable. Alpha helix present in the state before turning into a beta conformation.

17. A-Beta Plaques (3-Dimensional) Seen are only residues 18-42. 1-17 are not shown as they are disordered. Residues 18-42 form a beta strand, a turn, and another beta strand. Being parallel to one another (beta strands), the form beta sheets. Beta 1 and Beta 2 sheets are recognized on the left. Beta 2 Beta 1

18. Immunotherapy targeting A-Beta Plaques Antibody bound to residues 1-7 on Abeta.

19. Residues involved in Binding • Asp1 • Ala2 • Glu3 • Phe4 • Arg5 • His6 • Asp7

20. Beta-Secretase with Inhibitor PDB ID: 3IXJ

21. Beta-Secretase with Inhibitor • The following are the residues involved in the binding of the inhibitor: • Gly 34 • Tyr198 • Ile226 • Lys227 • Val332 • Thr329 • Targeted at BACE-1: the area where the beta-secretase cleaves the Amyloid precursor protein.

22. Current Treatments on the Market Fall into Two Categories: • Cholinesterase Inhibitors -Aricept - Tacrine - Donepezil - Rivastigmine - Galantamine 2. Amyloid Beta Clearing Agents • Dimebon (can also be classified as a Cholinesterase Inhibitor) • ELND005

23. Cholinesterase Inhibitors • Function to stop the breakdown of neurotransmitter Acetylcholine • Acetylcholine is important to brain function as it slows the break down of Acetylcholine – an important neurotransmitter that sends messages between cells • They only slow down the progression of the disease, not cure it completely

24. Acetyl-cholinesterase with Galantamine Galantamine is observed as the stick model in the center colored grey. The green are the residues with which it interacts. The protein seen in the background is Acetyl-cholinesterase. The red molecules floating are water.

25. Dimebon – Latripirdine Formally an antihistamine drug approved in Russia Inhibits Cholinesterase enzymes, NMDA receptors, and mitochondrial swelling caused by Abeta plaques. Acts to block mitochondrial pores Went through Phase III trials where it failed as it caused adverse side effects in humans. Seen as a drug that could have positive effects on Alzheimer’s and Huntington’s Disease. http://www.edinformatics.com/news/Dimebolin_150.jpg

26. ELN-D005 • A drug collaboration between Transitional Therapeutics, Inc. & Elan Pharmaceuticals, Inc. • In its second phase, which will finish in May 2010. • Orally administered – only for mild to moderate cases • Geared towards clearing the amyloid peptides in lieu of letting them form plaques in the brain.

27. Is there any permanent cure for this new age disease? Due to the fact that humans are living longer, will it have greater impacts on our society? Will we find a cure in the future?

28. Works Cited • http://www.transitiontherapeutics.com/technology/alzheimers.php • http://www.nytimes.com/2010/03/04/business/04drug.html • http://www.alzforum.org/drg/drc/detail.asp?id=111 • http://www.alz.org/alzheimers_disease_facts_figures.asp • www.medicalnewstoday.com/articles/126272.php • http://www.abpi.org.uk/publications/publication_details/targetAlzheimers/industry.asp