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Updated: Jul 18, 2026

Quantitative Measurement of γ-Secretase-mediated Amyloid Precursor Protein and Notch Cleavage in Cell-based Luciferase Reporter Assay Platforms
Published on: January 25, 2018
ATF4 regulates gamma-secretase activity during amino acid imbalance
Teruhiko Mitsuda1, Yoshika Hayakawa, Masanori Itoh
1Department of Neurobiology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
Abstract:
Accumulation of amyloid-beta (Abeta), 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 by activating transcription factor 4 (ATF4), regulated by GCN2 eukaryotic initiation factor 2alpha (eIF2alpha) 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 Abeta (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 eIF2alpha phosphorylation.
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