Alzheimer’s Disease

1. Alzheimer’s Disease A Geriatric Epidemic

2. Alzheimer’s Disease • Alzheimer’s disease currently affects between two and four million Americans. • Causes the degeneration of the nervous system over time • Two basic forms: • Early onset (under 65) • Late onset (65+)

3. History • The first person to make a diagnosis of Alzheimer’s disease was Alois Alzheimer (1864-1915). Alzheimer made the diagnosis on a fifty-one year old named Frau Auguste D. • A Belgian pathologist found amyloid to be a component of the plaques found in the brains of those with Alzheimer’s in the 1930’s.

4. Symptoms • Asking the same questions over and over again. • Repeating the same story, word for word, again and again. • Forgetting how to cook, or how to make repairs, or how to perform activities that were done with ease and regularity. • Getting lost in familiar surroundings, or misplacing household items. • Neglecting to complete everyday hygiene tasks. • Relying on someone else to make easy decisions.

5. Treatment • The drug tacrine helps to slow the degeneration process, but it is costly and causes numerous side effects including the buildup of the toxic liver enzyme alanine aminotransferase. • Like tacrine, other drugs can only delay the inevitable. • To date there is no cure for Alzheimer’s disease.

6. Alzheimer’s Physiology • Alzheimer’s disease is characterized by the presence of amyloid plaques and neurofibrillary tangles within the central nervous system. • The neurofibrillary tangles arrive as the result of defective tau proteins. • The plaques are derived from the buildup of β-amyloid protein, which in turn comes from amyloid precursor protein (APP).

7. Tau Proteins • Healthy tau proteins help to support microtubules in neurons. • Mutations on exon 10 on the mRNA strand coding for tau gives rise to 3 tau isoforms with four microtubule binding site instead of the usual three. • This interferes with the tau’s ability to interact with the microtubule. Instead the free tau begins to interact with itself and begins building tangles.

8. Neurofibrillary Tangle Formation

9. β-Amyloid Plaques • β-Amyloid is made from post-translational amyloid precursor protein (APP). • Two different enzymatic pathways exist for APP. • Three different pathways exist for the site of APP digestion and the formation of β-amyloid. • The formation of intracellular pools of β-amyloid contributes to the plaques characteristic of Alzheimer’s.

10. Enzymatic Pathways -Aβ40 vs. Aβ42

11. Three Sites of APP Digestion

12. Mutations Contributing to Plaques • Val717 mutation: increases ratio of Aβ42 to Aβ40 • Swedish mutation: mutation of amino acid 670 on APP from lysine to methionine along with amino acid 671 going from asparagine to lysine; increases use of β-secretase pathway • Presenilin mutation: increases ratio of Aβ42 to Aβ40

13. Cell Death

14. The Effect of Plaques on Action Potentials in the Nervous System

15. Closing Comments • Current research is looking to telomerase for a possible cure for Alzheimer’s. • Pathologists also hope that stem cells may provide a cure. • Alzheimer’s not only affects the patients but their families as well. It is a sad slow course that leaves relatives emotionally exhausted.

16. The End