Molecular mechanism of endoplasmic reticulum stress and Alzheimer disease

内质网应激与阿尔茨海默病的分子机制

• 批准号: 15591221
• 负责人: KUDO Takashi
• 金额: $ 2.18万
• 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: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591221/
• 关键词: Alzheimer disease; β-amyloid; endoplasmic reticulum stress; molecular chaperone; 小胞体; ストレス; Aβ; APP; カスペース; プロテオソーム; アポトーシス

Our previous reports showed that endoplasmic reticulum (ER) stress response was down-regulated in presenilin-1 mutant cells. Following the amyloid cascade hypothesis, we developed an interest in investigating the effects of ER stress on amyloid-β peptide (Aβ) generation. In the present study, we showed that treatment with an ER stressor resulted in the reduction of Aβ 40 and Aβ 42 generation. Immunocytochemical study and immunoblotting of subfractions showed that ER stress caused dislocation of amyloid precursor protein (APP) from late compartments to early compartments during the secretory pathway, and decreased levels of released Aβ by β and γ cutting despite no reduction of its secretase activities. Co-immunoprecipitation study showed that ER stress response facilitated binding of BiP/GRP78 to APP to be retained in early compartments, such as ER. In dominant-negative cells for ER stress, the reduction system of Aβ may deteriorate to cause relative accumulation of Aβ. These findings suggest that induction of BiP/GRP78 by ER stress may be one regulatory mechanism for Aβ generation.

我们以前的报告显示，内质网(ER)应激反应在早老素-1突变细胞中下调。根据淀粉样蛋白级联假说，我们对研究内质网应激对淀粉样蛋白β肽(Aβ)生成的影响产生了兴趣。在本研究中，我们发现内质网应激源治疗导致Aβ40和Aβ42代数减少。免疫细胞化学研究和亚组分免疫印迹表明，内质网应激导致淀粉样前体蛋白(APP)在分泌过程中从晚期隔室向早期隔室错位，并通过β和γ切割降低了释放的A DNA水平，尽管其分泌酶活性没有降低。免疫共沉淀研究表明，内质网应激反应促进Bip/GRP78与APP的结合，并保留在早期的隔室，如内质网。在内质网应激的显性负性细胞中，Aβ的还原系统可能恶化，导致Aβ的相对积累。这些发现提示，内质网应激诱导BIP/GRP78的表达可能是Aβ生成的一种调节机制。

项目成果

精神医学用語解説287.分子シャペロン

精神病学术语 287. 分子伴侣

• 发表时间: 2004
• 期刊: 臨床精神医学 33(11)
• 作者: 水野(松本)由子;鵜飼聡;他;工藤 喬
• 通讯作者: 工藤 喬

Manabe T et al.: "Induced HMGA1a expression causes aberrant splicing of Presenilin-2 pre-mRNA in sporadic Alzheimer's disease"Cell Death Differ.. 10. 698-708 (2003)

Manabe T 等人：“诱导 HMGA1a 表达导致散发性阿尔茨海默病中早老素 2 前体 mRNA 的异常剪接”细胞死亡差异.. 10. 698-708 (2003)

工藤 喬: "アミロイドカスケードをふまえたアルツハイマー病の治療戦略"分子精神医学. 4(1). 94-95 (2004)

Takashi Kudo：“基于淀粉样蛋白级联的阿尔茨海默氏病的治疗策略”《分子精神病学》94-95 (2004)。

Double-strand RNA dependent protein kinase (PER) is involved in the extrastriatal degeneration in Parkinson's disease and Huntington's disease

双链RNA依赖性蛋白激酶（PER）参与帕金森病和亨廷顿病的纹状体变性

• 发表时间: 2005
• 期刊: Neurochem Int 46
• 作者: Yoshio Bando;et al.
• 通讯作者: et al.

Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death.

• DOI: 10.1083/jcb.200310015
• 发表时间: 2004-05-10
• 期刊: JOURNAL OF CELL BIOLOGY
• 影响因子: 7.8
• 作者: Hitomi, Junichi;Katayama, Taiichi;Eguchi, Yutaka;Kudo, Takashi;Taniguchi, Manabu;Koyama, Yoshihisa;Manabe, Takayuki;Yamagishi, Satoru;Bando, Yoshio;Imaizumi, Kazunori;Tsujimoto, Yoshihide;Tohyama, Masaya
• 通讯作者: Tohyama, Masaya