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

Alzheimer’s Disease (AD) - symptoms 1)Synaptic dysfunction in neurons hippocampus and amygdala (memory) 2)Decrease in # neurons – ↓ACh oxidative damage, inflammation, apoptosis 3) Cognitive decline - loss of new memories, memory loss, dementia 4) Autopsy findings Plaque containing A  42 aggregates NFTs (neurofibrilary tangles – tau protein) 2 million Americans: 10% > 65; 50% > 85

APP – Amyloid  A4 Protein 1) Neuron cell surface receptor (753 aa) 2) Neuron growth, cell motility/adhesion, axon generation 3)APP processing: 671-  -secretase 711- or 713-  -secretase → A  40 or A  42 A  42 > A  40 ↑AD likelihood 4) A  42 & A  40 binds to apoE (apolipoprotein E) 50% apoE4 allele in AD vs. 20% 5) A  42 & A  40 binds and reduces Cu 2+ /Zn 2+

Alzheimer’s Disease (AD) – Genetic Predisposition Early onset AD ….. 10% of AD victims 1)Down Syndrome – APP is located on chromosome 21 or APP mutations 2) PSEN1 & PSEN2 mutants – encodes  -secretase ↑A  42 over A  40 Late onset AD ….. >2x increase if have apoE4 allele

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 A  42 and tau Calcium Hypothesis Presinilins are subunits of  -secretase Also function as ER Ca 2+ leak channels (independent of secretase activity) Defective presenilins lead to ↑Ca 2+ in ER evidence: abnormal Ca signaling in FAD patients with mutant presenilins

Alzheimer’s Disease (AD) – sequence The amyloid hypothesis? 1) APP → A  40 /A  42 faster than A  40/42 → aa: normal aging 2) A  42 oligomers accumulate in limbic cortexes 3) Synaptic dysfunction caused by A  42 oligomers? 4) A  plaque accumulation 5) Inflammation response in brain – microglial/astrocytes 6) Neuron dysfunction, oxidative stress, glutamate accumulation 7) Neurofibrillary tangles formed (tau) 8) 1 st symptoms - ↓neurons (apoptosis) - ↓ACh 9) Progressive cognitive decline → dementia

The Amyloid hypothesis A  42 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 A  oligomers↑. A  oligomers injected into rat brains inhibited LTP. Antibodies to A  oligomers enhanced LTP. Alternatives theories typically suggest multiple causes which include A  42 pathology but also include amyloid-independent mechanisms …. ↓NT release – altered signal transduction cascades – endo lysosomal trafficking deficiencies -

Alzheimer’s Disease (AD) – therapies AD detection problem 1) Ach esterase inhibitors 2)  -secretase inhibitors3)  -secretase inhibitors 4) A  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 A  42 clearance?

Donepezil (Aricept) Acetylcholine Esterase Inhibitors O acetyl choline || CH 3 -C-O-CH 2 -CH 2 -N(CH 3 ) 3 + Huperzine A

Ach esterase – Huperzine A complex

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 A  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,

Chadwick Article - prequiz 1. What was the primary conclusion of the article? 2.Describe the role of fMRI in the article? or …… What events were part of the film?

Cell Paper Amyloid aggregation sequesters proteins This results in loss of function failure to mount efficient stress response chromatin regulators (improper interactions with TFs) The  -protein interactors have certain characteristics large – flexible – disordered regions -