Analysis of the mechanism of pathological synaptic alterations in Alzheimer's disease

阿尔茨海默病病理性突触改变机制分析

• 批准号: 20300124
• 负责人: KINOSHITA Ayae
• 金额: $ 12.65万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 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-20300124/
• 关键词: アルツハイマー病; 老化; 神経変性; シナプス; 認知症; N-cadherin; インスリン; プレセニリン

We investigated the pathological mechanisms caused by mutations of Presenilin 1, a responsible protein for familial Alzheimer's disease(AD). We focused on insulin signaling as an influential factor of PS1 and revealed its effect on the localization and conformation of PS1. Our result showed that insulin inhibited GSK3 beta activation, thus leading to inhibition of PS1 phosphorylation and that insulin signaling is involved in the translocation of PS1 to the cell surface and its cleavage functions. Furthermore, we found that insulin receptor, IR, is cleaved by PS1, then its intracellular domain translocates to the nucleus, which activates transcription of Akt. Taken together, we conclude that insulin signaling is modulated by PS1. Next, we created a novel AD model mouse with diabetic condition by giving high fat diet to APP Tg mouse. This mouse showed a marked impairment of short-term memory, suggesting that diabetes is an aggravating factor for AD.

我们研究了早老素1突变引起的病理机制，早老素1是家族性阿尔茨海默病(AD)的主要致病蛋白。我们重点研究了胰岛素信号作为PS1的影响因素，揭示了它对PS1定位和构象的影响。我们的结果表明，胰岛素抑制了GSK3β的激活，从而抑制了PS1的磷酸化，并且胰岛素信号参与了PS1到细胞表面的移位及其切割功能。此外，我们还发现胰岛素受体IR被PS1切割，然后它的胞内区移位到细胞核，从而激活Akt的转录。综上所述，我们得出结论，胰岛素信号是由PS1调节的。接下来，我们通过给予APP-TG小鼠高脂饮食，建立了一种新型的糖尿病AD模型小鼠。这只小鼠表现出明显的短期记忆障碍，这表明糖尿病是阿尔茨海默病的加重因素。

项目成果

Insightinto"synaptopathy"in Alzheimer' sdisease : From lifestyle to PS1/N-cadherininteraction.

深入了解阿尔茨海默病中的“突触病”：从生活方式到 PS1/N-钙粘蛋白相互作用。

• 发表时间: 2011
• 期刊: Alz Dis Res J
• 作者: Kuzuya A;Kinoshita A;Uemura K.
• 通讯作者: Uemura K.

APPダイマー化におけるN-カドヘリンの影響

N-钙粘蛋白对 APP 二聚化的影响

• 发表时间: 2009
• 作者: 浅田めぐみ;植村健吾;葛谷聡;渡辺拡人;久保田正和;下濱俊;高橋良輔;木下彩栄
• 通讯作者: 木下彩栄

N-cadherin-based adhesion enhances Abeta release and decreased Abet a42/40 ratio

基于 N-钙粘蛋白的粘附增强 Abeta 释放并降低 Abet a42/40 比率

• 发表时间: 2009
• 期刊: Journal of Neurochemistry 156
• 作者: Uemura K;Lill CM;Banks M;Aoyagi N;Ando K;Kubota M;Kihara T;Nishimoto T;Sugimoto H;Takahashi R;Hyman BT;Shimohama S;Kinoshita A
• 通讯作者: Kinoshita A

Chronic cerebral hypoperfusion accelerates amyloid beta deposition in APPSwedish transgenic mouse

慢性脑灌注不足加速APPS瑞典转基因小鼠β淀粉样蛋白沉积

• 发表时间: 2009
• 期刊: Brain Research 1294
• 作者: Kitaguchi H;Tomimoto H;Ihara M;Shibata M;Uemura K;Kalaria RN;Kihara T;Asada-Utsugi M;Kinoshita A;Takahashi R
• 通讯作者: Takahashi R

細胞内たんぱく質分解系がPS1によるAPPの切断に及ぼす影響の検討

检查细胞内蛋白水解系统对 PS1 裂解 APP 的影响

• 发表时间: 2009
• 作者: 渡辺拡人;葛谷聡;浅田めぐみ;植村健吾;渡辺拡人;前迫真人;久保田正和;高橋良輔;木下彩栄
• 通讯作者: 木下彩栄