ATF4 regulates γ-secretase activity during amino acid imbalance

Accumulation of amyloid-β (Aβ), which is generated from amyloid precursor protein by γ-secretase, in cerebral cortex is common and critical incident in Alzheimer disease. Specifically, presenilin is an essential for γ-secretase activity. However, the regulation of presenilin expression, affecting γ-secretase activity, remains obscure. We investigated mechanism controlling the expression of presenilin-1 (PS1) and γ-secretase activity. We showed that PS1 is induced by activating transcription factor 4 (ATF4), regulated by GCN2 eukaryotic initiation factor 2α (eIF2α) kinase. A chromatin immunoprecipitation analysis and an electrophoretic mobility shift assay demonstrated that ATF4 binds to the regulatory region of human PS1 gene. Through knockdown analysis, we observed that the secretion of Aβ (1–42) and induction of γ-secretase cofactors are controlled by ATF4. These data indicate that ATF4 is critical for γ-secretase activity, by which ATF4 mRNA is preferentially translated in response to eIF2α phosphorylation.