NE102 Lecture Notes 3

Researchers could now generate anti a antibodies to

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Researchers could now generate anti- A  antibodies to study A . β β Researchers could infer the DNA sequence that would encode A  and use it to search β   for its gene – the Alzheimer’s gene? Identification of the gene encoding A : Amyloid Precursor Protein (APP) β Single-pass transmembrane protein Highly expressed in brain, predominantly in neurons Specifically in cell bodies, neurites, at synapses Present at plasma membrane & intracellular compartments Apparent roles in: Neuronal outgrowth Synaptic development, function, & maintenance A  sequence right by the lumen β
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Finding the Molecular Cause of Alzheimer Disease 18:04 A  is derived from cleavage of APP β Cell culture experiments defined two “pathways” of APP cleavage: Non-amyloidogenic Does not generate A β APP gets cleaved towards center of A  sequence β Secreted APP α APP C-terminal fragment   (C83) α Cleavage happens by  -secretase α AICD (APP intracellular domain) ϒ -secretase p3 AICD Amyloidogenic Generates A β APP gets cleaved at the N-terminal side of the A  sequence β Secreted APP β APP C-terminal fragment   (C99) β Cleavage happens by  -secretase (BACE1) β   ϒ -secretase A β AICD
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Finding the Molecular Cause of Alzheimer Disease 18:04 - ϒ secretase 4-subunit protein complex Pen-2 Presenilin, Nicastrin, Aph-1 Presenilin = the catalytic subunit that cleaves APP-CTFs DAPT = drug that inhibits  ϒ -secretase Blocks A  production β Accumulates APP-CTFs IMPORTANT POINT: A  is continuously generated & cleared in healthy brain β In AD brain, A  aggregates  β A  aggregation occurs in a stepwise manner β Monomers aggregate into soluble dimers & trimmers Dimers & trimers form into heterogeneous oligomeric assemblies (A  oligomerization) β Form into protofibrils Protofibrils form into insoluble fibrils Numerous studies have demonstrated that soluble A  oligomers are toxic to neurons β   when treated in culture or injected into intact mouse/rat brains Ongoing amyloid hypothesis: Misregulation of A  metabolism – Toxic A  oligomerization – A  deposition – β β β   neurodegeneration
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Finding the Molecular cause of AD pt. 2 18:04 Tangles – Aggregates of the  microtubule-associated protein tau REMINDER: Microtubule-associated proteins (MAPs) bind microtubules & regulate their  assembly, disassembly and stability Tau aggregates to form NFTs in neurons of Alzheimer brain Immunohistochemistry on AD hippocampal sections with   -tau antibody α QUESTION: Why does tau aggregate into NFTs during AD? Tau in NFTs is abnormally phosphorylated (aka  hyperphosphorylated ) Serine & Threonine residues phosphorylated on Tau within NFTs Ongoing Tau hypothesis: Misregulation of tau kinases (or phosphatases) – Tau  hyperphosphorylation – Toxic NFTs – Neurodegeneration OBVIOUS QUESTION: What causes synapse loss & neurodegeneration in AD?
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