Endoplasmic reticulum stress enhances γ-secretase activity

► ER stress induces expression of presenilin-1. ► Presenilin-1 induction is dependent on ATF4. ► ER stress upregulates γ-secretase activity and increases Aβ secretion. ► Quercetin suppresses ATF4 expression leading to decreased Aβ secretion. The endoplasmic reticulum (ER) copes with unfolded proteins in the lumen (ER stress) by activating three distinct intracellular signaling pathways of unfolded protein response (UPR). ER stress contributes to the pathogenesis of obesity and diabetes, which are risk factors for Alzheimer’s disease (AD) that accelerate the pathogenesis of AD. However, whether ER stress is involved in the development of AD remains unclear. In this study, we demonstrate that ER stress induces presenilin-1 expression through activating transcription factor 4 (ATF4), resulting in increased amyloid-β (Aβ) secretion by γ-secretase activity, which is suppressed by quercetin by modifying UPR signaling. This result suggests that ER stress may be stimulated in obesity and type 2 diabetes, thereby enhancing γ-secretase activity that is the underlying molecular mechanism affecting the pathogenesis of AD.