2. 2 Huntington’s disease Parkinson’s disease Amylotrophic lateral sclerosis Alzheimer’s Disease Neurodegenerative Disorders

3. Degenerative brain disorder developed in adulthood (brain cells die) Progressive and irreversible decline in memory and other cognitive abilities ~4.5 million people in America Some Facts

4. Forgetfulness and loss of smell Memory loss becomes more severe Language, perceptual, and motor skills deteriorate Mood becomes unstable Lost of mobility and control of body functions Death Symptoms http://www.alzheimers.org/rmedia/mediaroom.htm#animation

5. Diagnosis by exclusion –Medical history and mental status exams –Physical examination –Neurological exam –Blood count –CT, PET, and MRI scans to detect brain volume and activity Confirmed by autopsy Tau and β-amyloid test? Other developed tests have been unsuccessful Diagnosis

6. Genetics –Apolipoprotein E4 (APOE4) –Deletions in gene coding for α-macroglobulin (serum protease inhibitor) –LDL gene? Type II Diabetes Down Syndrome High cholesterol levels Stroke and previous head injuries Tobacco High homocysteine concentration in blood Risk Factors

7. Familial Alzheimer’s Disease –Caused by a genetic mutation –All are early onset (younger than 60 years) –Accounts for 10% of the cases Sporadic Alzheimer’s Disease –Most common (90% of the cases) –Typically occurs after age 65 Types

8. Older patients of Down’s syndrome also have neurofirillary tangles and senile plaques Martin, Joseph, N Engl J Med 1 1 Familial Autosomal AD

9. Amyloid hypothesis –β-amyloid protein tau hypothesis –tau protein Hypotheses http://www.alzheimers.org/rmedia/mediaroom.htm#animation

10. Appear first in the cerebral cortex Results from improper cleavage of APP Made by β-amyloid, tau, ubiquitin, α- antichymotrypsin, apolipoprotein E, presenilins 1 and 2, α-macroglobulin β-amyloid fragment (39 – 43 a.a.) is “sticky” and aggregates Forms intracellularly and transported outside of the neuron Senile Plaques http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12525689

11. Activates de immune system Disrupts neuron communication and inflammation β-amyloid facilitates Ca +2 entry to neurons Mitogen-Activated Protein Kinase (MAPK) Inhibits ubiquitin degradation Insufficient to cause cell death High metal concentration Senile Plaques APP Copper binding domain

12. Senile Plaques http://www.alzheimers.org/rmedia/mediaroom.htm#animation

13. Senile Plaques http://www.alzheimers.org/rmedia/mediaroom.htm#animation

14. Senile Plaques http://www.alzheimers.org/rmedia/mediaroom.htm#animation

15. Martin, Joseph, N Engl J Med known mutations Senile Plaques

16. Amyloid Tracer “Compound B” highlights β-amyloid Currently under human trials Developed at the University of Pittsburgh Sweden's Uppsala University University of Pittsburgh Medical Center

17. PIB Proc Natl Acad Sci U S A. 2003 October 14; 100(21): 12462–12467.

18. Presenilin 1 mutations Presenilin 2 mutations Martin, Joseph, N Engl J Med Presenilin

19. Astrocytes become more numerous and produce prostaglandin mediated inflammation Microglial cells produce free radicals –Produce InterLeukin-1β (IL-1β) and Tumor Necrosis-α (TNF-α) (inflammatory cytokines) –Induce enzymes like nitric oxide synthetase Inflammation damages neurons causing neuron death Astrocytes and Microglia Cells

20. Typically begin in the entorhinal cortex Visualized as paired helical filaments on electron microscopy tau protein maintains the structural integrity of microtubules within neurons In AD, tau protein becomes hyperphosporylated Hyperphosporylated tau binds to each other forming NFTs Neurons full of NFTs die Neurofibrillary Tangles

21. http://www.alzheimers.org/rmedia/mediaroom.htm#animation

22. NFTs not present in all cases NFTs kill output neurons mostly: –Cholinergic neurons (Ach) –Large pyramidal neurons –Output neurons in the hippocampus Neurofibrillary Tangles

23. Protein portion of lipoproteins (LDL, HDL, etc.) that transport cholesterol Synthesized in the liver, by the brain astrocytes, and oligodendrocytes Does not cross the Blood Brain Barrier Important risk factor Apolipoprotein

24. 299aa glycoprotein Acts as the binding site for LDL receptors –Allows lipids to get into the cell Major lipoprotein for lipid transport between neurons –cholesterol used for synapse plasticity and repair of damaged neurons Removes oxidized lipids from the brain Three common forms (E2, E3, and E4) Usually secreted after brain damage Apolipoprotein E

25. High insulin concentration stimulates nitric oxide synthetase –Combines nitric oxide with superoxide to produce peroxynitrite –Peroxynitrite causes Tyr nitration AD patients show high Tyr nitration in both neurons and glial cells Insulin

26. Nicotine in rats produces elevation of Nerve Growth Factor, enhancing Acetylcholine production and release Nicotine reduces β-amyloid production Incidence of AD is more than double for smokers compared to non-smokers Tobacco

27. Acetylcholinesterase inhibitors NMDA Receptor Antagonists –Memantine (Namenda) β-secretase (BACE) inhibitor? Anti-amyloid vaccine? Detoxification of β-amyloid? Metal ions reduction (Clioquinol)? Vitamin E intake Treatments

28. Regulate attention, the first stage of learning, and memory Use acetylcholine as a neurotransmitter Have more microtubules than other neurons Cholinergic Neurons

29. Breaks acetylcholine Promotes aggregation of β-amyloid Acetylcholineste rase + +H 2 O

30. Donepezil (Aricept) Galantamine (Reminyl) Rivastigmine (Exelon) Tacrine (Cognex) Acetylcholine AchE Inhibitors

31. Memantine/Auxura/Namenda Regulates Calcium influx Replaces Magnesium Ions NMDA Receptor Antagonist

32. Chelates copper and zinc in vitro Treatment reversed the deposition of amyloid in the brains of mice with AD Clioquinol cut amyloid deposits in half over a nine week period with no adverse effects. Clioquinol