Altered localization of amyloid precursor protein under endoplasmic reticulum stress

Recent reports have shown that the endoplasmic reticulum (ER) stress is relevant to the pathogenesis of Alzheimer disease. Following the amyloid cascade hypothesis, we therefore attempted to investigate the effects of ER stress on amyloid-β peptide (Aβ) generation. In this study, we found that ER stress altered the localization of amyloid precursor protein (APP) from late compartments to early compartments of the secretory pathway, and decreased the level of Aβ 40 and Aβ 42 release by β- and γ-cutting. Transient transfection with BiP/GRP78 also caused a shift of APP and a reduction in Aβ secretion. It was revealed that the ER stress response facilitated binding of BiP/GRP78 to APP, thereby causing it to be retained in the early compartments apart from a location suitable for the cleavages of Aβ. These findings suggest that induction of BiP/GRP78 during ER stress may be one of the regulatory mechanisms of Aβ generation.