P2‐271: Presenilin 1 (PS1) is required for lysosome acidification: FAD mutations of PS1 cause loss of protein turnover by autophagy

Autophagy pathology is exceptionally robust in AD, where AVs collect in massive numbers within grossly distended portions of axons and dendrites of affected neurons, likely reflecting defective AV clearance. This lysosome-related pathology, along with neuronal loss and amyloid deposition, are greatly accentuated in early-onset familial AD (FAD) due to mutations of PS1, the most common cause of FAD. However, underlying mechanisms are unknown. We used immunoblotting, immunocytochemistry, and ultrastructural (EM) approaches to define the role of presenilin 1 (PS1) in autophagic/lysosomal protein degradation in both cell culture and animal models. PS1 ablation specifically blocks substrate proteolysis and autophagosome clearance during macroautophagy by selectively preventing autolysosomes acidification and cathepsin activation. Neurons in mice hypomorphic for PS1 or conditionally depleted of PS1 display similar abnormalities. PS1 mutations causing early-onset AD produce a similar lysosomal/autophagy phenotype and partial loss of autophagy function as shown in fibroblasts from patients with familial AD. PS1 is essential for lysosome acidification and proteolysis during autophagy. Disruption of autophagy function by PS1 mutations promotes accumulation of pathogenic proteins and neuronal death in AD underscoring the significance of lysosomal system dysfunction in AD pathogenesis.