The amyloid hypothesis

Amyloid is a proteinaceous material that deposits both within neurons and as extracellular 'plaques' in brain tissue and is a hallmark (tombstone) neuropathological feature of AD.14 Two peptides, amyloid beta (Ab) peptide 1-40 (A^40) and 1-42 (Ab42), derived from proteolytic cleavage of amyloid precursor protein (APP), are major constituents of plaques. Genetic linkage studies in AD patients have identified mutations in APP (20 missense) and in presenilin proteins -1 (140 known) and -2 (10 known) that result in increased production of APP cleavage products. Ab peptides are hydrophobic, being derived from the transmembrane domain sequence of APP, and thus have a propensity to aggregate in aqueous environments. Ab peptides associate in a different conformations of increasing molecular weight and decreasing solubility: oligomers, Ab-derived diffusible ligands, protofibrils, and fibrils, all of which can interfere with neuronal function, elicit toxicity, and have the potential to elicit inflammatory cytokine production.15 Ab oligomers block long-term potentiation underlying memory consolidation.16 Different forms of Ab can activate cell surface receptors (e.g., a7 neuronal nicotinic receptors, p75 neurotrophin receptor, receptor for advanced glycosylation end-products; RAGE)17 and intracellular signaling pathways that culminate in neuronal cell death.18

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