Application of an ER chaperone inducer for Alzheimer disease

ER伴侣诱导剂在阿尔茨海默病中的应用

• 批准号: 20591403
• 负责人: KUDO Takashi
• 金额: $ 2.91万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20591403/
• 关键词: 小胞体ストレス; 分子シャペロン; 脳梗塞; アルツハイマー病; アポトーシス; 脳虚血; 急性毒性

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.

内质网 (ER) 应激反应是一种防御系统，用于处理 ER 腔内未折叠蛋白的积累。最近的报告表明，内质网应激与一些神经退行性疾病和脑缺血的病理有关。在筛选诱导 ER 介导的伴侣 BiP/GRP78 (BiP) 的化合物时，我们鉴定了 BiP 诱导物 X (BIX)。 BIX 优先诱导 BiP，并轻微诱导 GRP94、钙网蛋白和 CHOP。 BIX 对 BiP mRNA 的诱导是通过 ATF6 途径激活 BiP 基因上游的 ER 应激反应元件 (ERSE) 介导的。用 BIX 预处理神经母细胞瘤细胞可减少 ER 应激诱导的细胞死亡。 BIX 脑室内预处理减少了小鼠局灶性脑缺血引起的梗塞面积。在 BIX 处理小鼠的半暗带中，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。综合考虑这些结果，BIX 似乎诱导 BiP 来防止 ER 应激引起的神经元死亡，这表明它可能是 ER 应激引起的脑部疾病的潜在治疗剂。

项目成果

A Novel Therapeutic strategy for Alzheimer disease by amolecular chaperone inducer

分子伴侣诱导剂治疗阿尔茨海默病的新策略

• 发表时间: 2008
• 作者: T. Kudo;K. Imaizumi;H. Hara;T. Tabira;M. Takeda
• 通讯作者: M. Takeda

Regulation of ER molecular chaperone prevents bone loss in a murine model for osteoporosis

• DOI: 10.1007/s00774-009-0117-z
• 发表时间: 2010-03-01
• 期刊: JOURNAL OF BONE AND MINERAL METABOLISM
• 影响因子: 3.3
• 作者: Hino, Shin-ichiro;Kondo, Shinichi;Imaizumi, Kazunori
• 通讯作者: Imaizumi, Kazunori

小胞体-プロテアソーム系に基づく神経変性疾患の新しい治療戦略

基于内质网-蛋白酶体系统的神经退行性疾病治疗新策略

• 发表时间: 2009
• 作者: 工藤喬;今泉和則
• 通讯作者: 今泉和則

THE IMPACT OF A GENOME-WIDE SUPPORTED PSYCHOSIS VARIANT IN THE ZNF804A GENE ON MEMORY FUNCTION IN SCHIZOPHRENIA

• DOI: 10.1016/j.schres.2010.02.1032
• 发表时间: 2010-04
• 期刊: Schizophrenia Research
• 影响因子: 4.5
• 作者: R. Hashimoto;K. Ohi;Y. Yasuda;M. Fukumoto;M. Iwase;N. Iike;M. Azechi;K. Ikezawa;Masahiko Takaya;Hidetoshi Takahashi;H. Yamamori;R. Ishii;H. Kazui;N. Iwata;M. Takeda

SORL1 is genetically associated with Alzheimer disease in a Japanese population

• DOI: 10.1016/j.neulet.2009.06.014
• 发表时间: 2009-09-11
• 期刊: NEUROSCIENCE LETTERS
• 影响因子: 2.5
• 作者: Kimura, Ryo;Yamamoto, Mitsuko;Takeda, Masatoshi
• 通讯作者: Takeda, Masatoshi