Neurodegenerative Disorders

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

3. Some Facts • 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

4. Symptoms • 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 http://www.alzheimers.org/rmedia/mediaroom.htm#animation

5. Diagnosis • 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

6. Risk Factors • 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

7. Types • 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

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

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

10. Senile Plaques • 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 http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12525689

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

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

19. Astrocytes and Microglia Cells • 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

20. Neurofibrillary Tangles • 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

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

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

23. Apolipoprotein • 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

24. Apolipoprotein E • 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

25. Insulin • 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

26. Tobacco • 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

27. Treatments • 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

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

29. +H2O + Acetylcholinesterase • Breaks acetylcholine • Promotes aggregation of β-amyloid

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

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

32. Clioquinol • 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.