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

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