Accumulation of amyloid-beta (A beta), which is generated from amyloid precursor protein by gamma-secretase, in cerebral cortex is common and critical incident in Alzheimer disease. Specifically, presenilin is an essential for gamma-secretase activity. However, the regulation of presenilin expression, affecting gamma-secretase activity, remains obscure. We investigated mechanism controlling the expression of presenilin-1 (PS1) and gamma-secretase activity. We showed that PS1 is induced gamma activating transcription factor 4 (ATF4), regulated by GCN2 eukaryotic initiation factor 2 alpha (eIF2 alpha) 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 A beta (1-42) and induction of gamma-secretase cofactors are controlled by ATF4. These data indicate that ATF4 is critical for gamma-secretase activity, by which ATF4 mRNA is preferentially translated in response to eIF2 alpha phosphorylation. (c) 2006 Elsevier Inc. All rights reserved.