Investigation of the synaptic dissociation mechanism

突触分离机制的研究

• 批准号: 18500263
• 负责人: KINOSHITA Ayae
• 金额: $ 2.57万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18500263/
• 关键词: Alzheimer's disease; presenilin; synapse; phosphorylation; signal transduction; cadherin; catenin; シナプス可塑性; N-cadherin

In order to investigate the mechanism of synaptic dissociation which underlies the synaptic plasticity, we focused on the functions of neuronal adhesion molecules, N-cadherin. N-cadherin is an adhesion molecule, which adheres synaptic clefts in the brain. These adhesion molecules are recently reported to cleaved by several secretases, such as gamma-secretase. After the cleavage in the membranous portion, its cytoplasmic fragment is released into the cytoplasm and enters the nucleus, then plays a role as a modulator of the transactivation. This process is called "Regulated intramembrane proteolysis (RIP)". By using the mouse primary neurons we confirmed that N-cadherin was actually cleaved by some stimuli, and the translocation of its cytoplasmic fragment upregulation of beta-catenin which is an essential molecule for neuronal growth and differentiation. We speculated that this process is also important in vivo, so to confirm in vivo relevancy, we started to generate mutant PS1 (gamma-secretase)-knock-in mouse in which N-cadherin is not cleaved by gamma-secretase. We have already got the F1 hetero mouse. We hope this study will reveal a new insight into synaptic dissociation caused by secretase-mediated cleavages. We would like to deepen this result and hope to elucidate the underlying mechanism of synaptic plasticity. Since gamma-secretase is one of the important targets for the treatment of Alzheimer's disease, our research may help us understand the pathological mechanism of Alzheimer's disease.

为了探讨突触可塑性的基础--突触分离的机制，我们着重研究了神经元粘附分子N-钙粘蛋白的功能。N-钙粘蛋白是一种粘附分子，其粘附脑中的突触裂隙。最近报道这些粘附分子被几种分泌酶切割，如γ-分泌酶。在膜部分裂解后，其胞质片段释放到细胞质中并进入细胞核，然后起反式激活的调节剂的作用。这个过程被称为“调节性膜内蛋白水解（RIP）”。通过使用小鼠原代神经元，我们证实了N-钙粘蛋白实际上被一些刺激物切割，并且其胞质片段的易位上调β-连环蛋白，其是神经元生长和分化的必需分子。我们推测该过程在体内也是重要的，因此为了确认体内相关性，我们开始产生其中N-钙粘蛋白不被γ-分泌酶切割的突变PS1（γ-分泌酶）-敲入小鼠。我们已经有了F1异种小鼠。我们希望这项研究将揭示一个新的见解突触解离所造成的分泌酶介导的裂解。我们希望深化这一结果，并希望阐明突触可塑性的潜在机制。由于γ-分泌酶是治疗阿尔茨海默病的重要靶点之一，我们的研究可能有助于我们了解阿尔茨海默病的病理机制。

项目成果

N-cadherin enhances extracellular secretion of Abeta and modulates Abeta42/40 ratio

N-钙粘蛋白增强 Abeta 的细胞外分泌并调节 Abeta42/40 比率

• 发表时间: 2007
• 作者: 植村健吾;青柳信寿;安藤功一;高橋良輔;下濱俊;木下彩栄
• 通讯作者: 木下彩栄

高齢者介護における精神的問題

老年人护理中的心理问题

• 发表时间: 2008
• 作者: 日吉和子;カール・ベッカー;木下彩栄
• 通讯作者: 木下彩栄

The effect of amyloid beta protein on cadherin cleavage

β淀粉样蛋白对钙粘蛋白裂解的影响

• 发表时间: 2007
• 作者: Uemura;K.;Aoyagi;N.;Ando;K.;Takahashi;R.;Shimohama;S.;Kinoshita;A
• 通讯作者: A

Modulation of beta-catenin nuclear signaling via epsilon-cleavage of N-cadherin.

通过 N-钙粘蛋白的 ε 切割调节 β-连环蛋白核信号传导。

• 发表时间: 2006
• 期刊: Biochem Biophys Res Commun 345
• 作者: Uemura;K.;Kihara T.;Kuzuya;A.;Okawa;K.;Bito H;Ninomiya H;Sugimoto H;Kinoshita;A*;Shimohama S.* (*shared last author)
• 通讯作者: Shimohama S.* (*shared last author)

細胞の接着状態によるgammaセクレターゼの構造と切断機能の調節

根据细胞粘附状态调节γ分泌酶结构和裂解功能

• 发表时间: 2007
• 作者: Uemura;K.;Kihara T.;Kuzuya;A.;Okawa;K.;Bito H;Ninomiya H;Sugimoto H;Kinoshita;A*;Shimohama S.* (*shared last author);木下彩栄
• 通讯作者: 木下彩栄