Autophagy impairment stimulates PS1 expression and gamma-secretase activity.

γ-Secretase plays an important role in the development of Alzheimer disease (AD). γ-Secretase activity is enriched in autophagic vacuoles and it augments amyloid-β (Aβ) synthesis. Autophagy-lysosomal dysfunction has been implicated in AD, but whether γ-secretase activity is affected by autophagy remains unclear. Here we report that γ-secretase activity is enhanced in basal autophagy-disturbed cells through the α subunit of eukaryotic translation initiation factor 2 (eIF2α) kinase, general control nonderepressible 2 (GCN2). Presenilin-1 (PS1) expression was increased even in the presence of nutrients in autophagy-related 5 knockdown (Atg5KD) human embryonic kidney (HEK293) cells expressing a short hairpin RNA as well as in chloroquine-treated HEK293 cells. However, PS1 expression induction was prevented in GCN2KD and ATF4KD cells. Furthermore, Atg5KD cells showed an increase in Aβ production and Notch1 cleavage. These were reduced by an autophagy inducer, resveratrol. Thus, we conclude that the autophagy-l...