Analysis of underlying mechanism to develop Alzheimer's disease

阿尔茨海默病发病机制分析

• 批准号: 23617007
• 负责人: NAKAGAWA Toshiyuki
• 金额: $ 3.49万
• 依托单位: Gifu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23617007/
• 关键词: 小胞体ストレス; ATF4; GADD34; eIF2alpha; アミロイドーベータ; eIF2α; アミロイド-β; PERK; GCN2; アミロイドｰβ; メタボリック症候群; 肥満; 糖尿病

Gamma-secretase produces amyloid-beta (Ab) in the brain from Ab precursor protein, which is critical for tha pathogenesis of Alzheimer's disease (AD). The endoplasmic reticulum (ER) stress causes unfolded proteins, which are processed by unfolded protein response (UPR). Pathogenesis of obesity and diabetes, which are risk factors for AD, is related to ER stress. However, whether ER stress is engaged in the development of AD remains obscure. In this research, I showed that ER stress activated gamma-secretase, leading to augmentation of Ab through induction of activating transcription factor 4 (ATF4). Ab secretion was repressed in vitro by quercetin, which induced the growth arrest and DNA damaged-inducible gene (GADD)34. In addition, we found that phosphorylated eIF2alpha and ATF4 were increased in the brain of AD model mice APP23. These results suggest that ER stress signaling may be disturbed in the brain of AD.

γ-分泌酶在脑内将β-淀粉样蛋白（Ab）前体蛋白转化为Ab，在阿尔茨海默病（AD）的发病机制中起重要作用。内质网（ER）应激引起未折叠蛋白，其通过未折叠蛋白反应（UPR）加工。肥胖和糖尿病是AD的危险因素，其发病机制与内质网应激有关。然而，ER应激是否参与AD的发展仍不清楚。在这项研究中，我发现ER应激激活γ-分泌酶，通过诱导激活转录因子4（ATF 4）导致抗体增加。抗体分泌在体外抑制槲皮素，诱导生长停滞和DNA损伤诱导基因（GADD）34。此外，我们发现在AD模型小鼠APP 23的脑中磷酸化eIF 2 α和ATF 4增加。这些结果表明，ER应激信号可能在AD的脑中受到干扰。

项目成果

A novel regulation mechanism of synaptic transmission by preseynapse-localizing Caymanataxia-related protein,Caytaxin

突触前定位的 Caymanataxia 相关蛋白 Caytaxin 调节突触传递的新机制

• 发表时间: 2011
• 作者: Masanori itoh;Shimo Li;Kazunori Ohta;Masashi Ueda;Yoko Hida;Yoshihiro Suzuki;Eri Ohta;Akihito Mizuno;Miao-xing Wang;Toshiyuki Nakagawa
• 通讯作者: Toshiyuki Nakagawa

Molecular cloning and sequence analysis of an extracellular protease from four bacillus strains

四种芽孢杆菌胞外蛋白酶的分子克隆和序列分析

• 发表时间: 2013
• 期刊: Biosci. Biotechnol. Biochem
• 作者: Xujun Han;Yuh Shiwa;Masanori Itoh;Tohru Suzuki;Hirofumi Yoshikawa;Toshiyuki Nakagawa;Hiroko Nagano
• 通讯作者: Hiroko Nagano

Molecular cloning and sequence analysis of an extracellular protease from four bacillus strains.

四种芽孢杆菌菌株胞外蛋白酶的分子克隆和序列分析。

• 发表时间: 2013
• 期刊: Biosci. Biotechnol. Biochem.
• 作者: Xujun Han;Yuh Shiwa;Masanori Itoh;Tohru Suzuki;Hirofumi Yoshikawa;Toshiyuki Nakagawa;Hiroko Nagano.
• 通讯作者: Hiroko Nagano.

Miao-xing Wang, ToshiyukiNakagawa. Olfaxin as a novel Prune2 isoform predominantly expressed in olfactory system

王淼兴，中川敏之。

• 发表时间: 2012
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Shimo Li;YoshikaHayakawa-Yano;MasanoriItoh;MasashiUeda;Kazunori Ohta;YoshihiroSuzuki;AkihitoMizuno;EriOhta;YokoHida
• 通讯作者: YokoHida

認知症

失智

• 发表时间: 2021
• 期刊: 臨床と研究
• 作者: 原英夫