Presenilin 1 Mutations Converge on Aβ42/Aβ40 Elevation via Distinct Mechanisms

ABSTRACT Mutations in Presenilin 1 (PS1) are the most common genetic cause of familial Alzheimer's disease (AD). However, the exact mechanisms by which these mutations alter amyloid precursor protein (APP) processing and drive amyloid β (Aβ) production remain unclear. In this study, five PS1 mutations (M146V, G384A, C410Y, Y115H, and the Notch‐sparing mutation ΔS169) were transfected into neuroblastoma cells lacking endogenous PS1/PS2 expression and human embryonic kidney cells stably overexpressing either wild‐type APP or the APP Swedish mutation. We investigated the effects of these mutations on APP processing, Aβ42/Aβ40 ratio, cytotoxicity, BACE1 expression, and PS1 endoproteolysis. Our results demonstrate that PS1 mutations differentially modulate APP processing, producing distinct Aβ profiles independent of their effects on Notch signaling. All mutations increased the Aβ42/Aβ40 ratio, while BACE1 levels were unchanged and no direct PS1‐BACE1 interactions were found. All mutations increased cytotoxicity, whereas only the Notch‐impairing mutations reduced cell viability, suggesting impaired Notch signaling may contribute to this effect. Lastly, the mutations exhibited distinct endoproteolytic rates that correlated only with APP‐C83 levels. These findings provide novel insights into how distinct PS1 mutations impact amyloid pathology.