Alzheimer’s Disease

1. Alzheimer’s Disease Find group of ~4 students ~ 10 minutes Discuss the following personal family connection to AD (if willing only) observations/experiences with AD Perception regarding ….. cause diagnosis treatments prevention

2. Alzheimer’s Disease (AD) - symptoms • Synaptic dysfunction in neurons • hippocampus and amygdala (memory) • Decrease in # neurons – ↓ACh • oxidative damage, inflammation, apoptosis 3) Cognitive decline - loss of new memories, memory loss, dementia 4) Autopsy findings Plaque containing Ab42 aggregates NFTs (neurofibrilary tangles – tau protein) 2 million Americans: 10% > 65; 50% > 85

3. APP – Amyloid b A4 Protein 1) Neuron cell surface receptor (753 aa) 2) Neuron growth, cell motility/adhesion, axon generation • APP processing: • 671- b-secretase • 711- or 713- g-secretase → Ab40 or Ab42 • Ab42 > Ab40↑AD likelihood 4) Ab42 & Ab40 binds to apoE (apolipoprotein E) 50% apoE4 allele in AD vs. 20% 5) Ab42 & Ab40 binds and reduces Cu2+/Zn2+

4. Alzheimer’s Disease (AD) – Genetic Predisposition Early onset AD ….. 10% of AD victims • Down Syndrome – APP is located on chromosome 21 • or APP mutations 2) PSEN1 & PSEN2 mutants – encodes g-secretase ↑Ab42 over Ab40 Late onset AD ….. >2x increase if have apoE4 allele

5. Tau protein & Tau hypothesis Tau binds to tubulin and helps to stabilize microtubules microtubules are important to axon function in neurons tau phosphorylation important to function) hyperphosphorylation induces tangles Debates over cause/effect relationship between Ab42 and tau Calcium Hypothesis Presinilins are subunits of g-secretase Also function as ER Ca2+ leak channels (independent of secretase activity) Defective presenilins lead to ↑Ca2+ in ER evidence: abnormal Ca signaling in FAD patients with mutant presenilins

6. Alzheimer’s Disease (AD) – sequence The amyloid hypothesis? 1) APP → Ab40/Ab42 faster than Ab40/42 → aa: normal aging 2) Ab42 oligomers accumulate in limbic cortexes 3) Synaptic dysfunction caused by Ab42 oligomers? 4) Ab plaque accumulation 5) Inflammation response in brain – microglial/astrocytes 6) Neuron dysfunction, oxidative stress, glutamate accumulation 7) Neurofibrillary tangles formed (tau) 8) 1st symptoms - ↓neurons (apoptosis) - ↓ACh 9) Progressive cognitive decline → dementia

7. The Amyloid hypothesis Ab42 oligomers is the causative agent in AD In animal models dementia correlates poorly with plaque increased tau tangles cause Parkinson’s-like symptoms. AD symptoms↑ as diffusible forms of Aboligomers↑. Aboligomers injected into rat brains inhibited LTP. Antibodies to Aboligomers enhanced LTP. Alternatives theories typically suggest multiple causes which include Ab42 pathology but also include amyloid-independent mechanisms …. ↓NT release – altered signal transduction cascades – endo lysosomal trafficking deficiencies -

8. Alzheimer’s Disease (AD) – therapies AD detection problem 1) Ach esterase inhibitors 2) b-secretase inhibitors 3) g-secretase inhibitors 4) Ab oligomer antibodies 5) Anti-inflamatory drugs – e.g. NSAIDs 6) Statins – cholesterol lowering drugs (also anti-inflammatory) 7) Anti-oxidants – protect neurons & avoid inflammation 8) NMDA-R antagonists – counteract ↑glutamate 9) Chelating agents – aid in Ab42 clearance?

9. Acetylcholine Esterase Inhibitors Donepezil (Aricept) Huperzine A O acetyl choline || CH3-C-O-CH2-CH2-N(CH3)3+

10. Ach esterase – Huperzine A complex

11. How to avoid AD? Anti-hypertensive medication? Keep BP down Nutrition – 3 fatty acids – LDL↓ - weight↓ DHA protects against learning deficits in rat AD models in vitro – DNA inhibits Ab fiber formation. Cognitive engagement – i.e. think!! Physical activity Why? 1 – prevents inflammation? 2 – healthy brain chemistry 3 – stimulates neural cell growth 4 – keeps BP/weight/LDL down,