Application of an ER chaperone inducer for Alzheimer disease

内质网（ER）应激反应是一种防御系统，用于处理内质网腔内未折叠蛋白的积累。近年来的研究表明，内质网应激参与了一些神经退行性疾病和脑缺血的病理过程。在筛选诱导ER介导的伴侣蛋白BiP/GRP 78（BiP）的化合物时，我们鉴定了BiP诱导剂X（BIX）。BIX优先诱导BiP，轻微诱导GRP 94、钙网蛋白和CHOP。BIX对BiP mRNA的诱导是通过激活BiP基因上游的ER应激反应元件（ERSE）介导的，通过ATF 6途径。用BIX预处理神经母细胞瘤细胞减少了由ER应激诱导的细胞死亡。脑室内预处理BIX可减少小鼠局灶性脑缺血引起的梗死面积。在BIX处理小鼠的半影区，ER应激诱导的细胞凋亡被抑制，导致凋亡细胞数量减少。综合考虑这些结果，BIX似乎诱导BiP防止由ER应激引起的神经元死亡，这表明它可能是由ER应激引起的脑疾病的潜在治疗剂。

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 some neurodegenerative diseases and cerebral ischemia. 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. 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 cerebral diseases caused by ER stress.