Amyloid-independent pathogenesis for Alzheimer’s disease: implications for drug design

Abstract

Alzheimer’s disease (AD) is characterized pathologically by cerebral deposits of the amyloid β-peptide (Aβ), particularly the aggregation prone 42-residue variant Aβ42. The amyloid hypothesis of AD pathogenesis, which has dominated the field for over 30 years, posits that Aβ42 aggregation triggers a cascade of events culminating in neurodegeneration. Strong support of the amyloid hypothesis includes genetic mutations that cause early-onset familial AD (FAD), which are found in the amyloid precursor protein (APP) and in presenilin and alter Aβ production or properties. Presenilin is the catalytic component of γ-secretase, which cleaves APP substrate to produce Aβ peptides; thus, all FAD mutations are in the substrate and enzyme that generates Aβ. Nevertheless, how Aβ42 triggers neurodegeneration remains unclear, and recently approved therapeutics targeting Aβ are modestly effective at best, suggesting Aβ may not be the primary disease driver. Recent studies suggest that FAD mutations result in stalled γ-secretase enzyme-substrate (E-S) and that these stalled complexes can trigger synaptic degeneration in the absence of Aβ production. These findings suggest that drug discovery efforts should focus on rescuing stalled γ-secretase E-S complexes and deficient enzyme activity.