Beyond the Amyloid Hypothesis: Proteolytic Dysfunction in Familial Alzheimer's Disease

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Michael S. Wolfe

Abstract

For over 30 years, the amyloid hypothesis of Alzheimer’s disease has dominated this field of biomedical investigation. The hypothesis posits that aggregation of the amyloid β-peptide (Aβ) in the brain triggers a cascade of events that ultimately lead to neurodegeneration and cognitive decline. Early genetic and biochemical evidence supported a critical role of Aβ, particularly the 42-residue form Aβ42: Dominant missense mutations in the substrate (amyloid precursor protein, APP) and enzyme (γ-secretase) that produce Aβ cause early-onset familial Alzheimer’s disease (FAD). Nevertheless, serious gaps remain in understanding pathogenic pathways, and despite intense efforts over many years, effective agents for Alzheimer’s disease have been elusive. Here I discuss recent efforts to elucidate precisely how FAD mutations alter the complex proteolytic processing of APP substrate by γ-secretase, with results suggesting pathogenic triggers other than Aβ42.

Key words: amyloid β-peptide, presenilin, γ-secretase, proteolysis

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How to Cite
WOLFE, Michael S.. Beyond the Amyloid Hypothesis: Proteolytic Dysfunction in Familial Alzheimer's Disease. Medical Research Archives, [S.l.], v. 10, n. 8, aug. 2022. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/3013>. Date accessed: 07 oct. 2022. doi: https://doi.org/10.18103/mra.v10i8.3013.
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Research Articles