[Therapeutic strategies for Alzheimer disease based on endoplasmic reticulum stress]

The endoplasmic reticulum (ER) stress response is a defense system for dealing with the accumulation of unfolded proteins in the ER lumen. Recent reports have shown that ER stress is involved in the pathology of Alzheimer disease and some neurodegenerative diseases. In a screen for compounds that induce the ER-mediated chaperone BiP/GRP78 (BiP), we identified BiP inducer X (BIX). BIX preferentially induced BiP with slight inductions of GRP94, calreticulin, and CHOP. The induction of BiP mRNA by BIX was mediated by activation of ER stress response elements (ERSEs) upstream of the BiP gene, through the ATF6 pathway. 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, good in vivo models of ER stress. In the penumbra of BIX-treated mice, ER stress-induced apoptosis was suppressed, leading to a reduction in the number of apoptotic cells. Considering these results together, it appears that BIX induces BiP to prevent neuronal death by ER stress, suggesting that it may be a potential therapeutic agent for Alzheimer disease and some neurodegerenerative diseases caused by ER stress.