Implication of ER stress in amyloid production and its application for therapeutic approach

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Recent reports have shown that ER stress is involved in the pathology of some neurodegenerative diseases. In a screen for compounds that induce the ER-mediated chaperone BiP/GRP 78 (BiP), we identified BiP inducer X (BIX). BIX induced BiP only, in a dose-dependent manner, without induction of other molecules involved in the ER stress response. Pretreatment of neuroblastoma cells with BIX reduced cell death induced by ER stress. Intracerebroventricular pretreatment with BIX reduced the area of infarction due to focal cerebral ischemia in mice. In the penumbra of BIX-treated mice, ER stress-induced apoptosis was suppressed, leading to a reduction the number of apoptotic cells.According to our report, BiP binds amyloid precursor protein (APP) to alter the localization of APP to early compartments of the secretory pathway and reduce A β production. In this study, we showed that BIX reduced A β production by its BiP induction property. Taken together, BIX may be a potential therapeutic agent for Alzheimer disease.