Autophagy impairment stimulates PS1 expression and γ-secretase activity

gamma-Secretase plays an important role in the development of Alzheimer disease (AD). gamma-Secretase activity is enriched in autophagic vacuoles and it augments amyloid-beta (A beta) synthesis. Autophagy-lysosomal dysfunction has been implicated in AD, but whether gamma-secretase activity is affected by autophagy remains unclear. Here we report that gamma-secretase activity is enhanced in basal autophagy-disturbed cells through the a subunit of eukaryotic translation initiation factor 2 (eIF2 alpha) kinase, general control nonderepressible 2 (GCN2). Presenilin-1 (PS1) expression was increased even in the presence of nutrients in autophagy-related 5 knockdown (Atg5(KD)) 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 GCN2(KD) and ATF4(KD) cells. Furthermore, Atg5(KD) cells showed an increase in A beta production and Notch1 cleavage. These were reduced by an autophagy inducer, resveratrol. Thus, we conclude that the autophagy-lysosomal system regulates gamma-secretase activity through GCN2.