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

最近的研究表明，内质网应激参与了一些神经退行性疾病的病理过程。在对诱导内质网介导的伴侣蛋白Bip/GRP 78(Bip)的化合物的筛选中，我们确定了Bip诱导剂X(Bix)。Bix仅以剂量依赖的方式诱导Bip，而不诱导参与内质网应激反应的其他分子。Bix处理神经母细胞瘤细胞可减少内质网应激诱导的细胞死亡。侧脑室注射Bix可减少小鼠局灶性脑缺血所致的脑梗塞面积。在Bix处理的小鼠半暗带中，内质网应激诱导的细胞凋亡受到抑制，导致凋亡细胞数量减少。根据我们的报告，Bip与淀粉样前体蛋白(APP)结合，改变APP的定位到分泌途径的早期区段，并减少Aβ的产生。在这项研究中，我们证明了Bix通过其BiP诱导特性减少了Aβ的产生。综上所述，Bix可能是治疗阿尔茨海默病的潜在药物。

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.