Investigation of the synaptic dissociation mechanism

为了研究突触可塑性背后的突触解离机制，我们重点研究了神经元黏附分子N-钙粘附素的功能。N-钙粘附素是一种黏附分子，它能黏附大脑中的突触裂隙。据报道，这些黏附分子最近被几种分泌酶切割，如伽马分泌酶。在膜部分被切割后，其胞质片段被释放到细胞质并进入细胞核，然后起到反式激活的调节作用。这个过程被称为“调节膜内蛋白分解(RIP)”。利用小鼠原代神经元，我们证实了N-钙粘蛋白确实被某些刺激所切割，其胞浆片段的移位上调了β-连环蛋白的表达，而β-连环蛋白是神经元生长和分化所必需的分子。我们推测这一过程在体内也很重要，因此为了证实体内相关性，我们开始培育突变体PS1(伽马分泌酶)敲入小鼠，在该突变体中N-钙粘素不被伽马分泌酶切割。我们已经有了F1异种鼠标。我们希望这项研究能对分泌酶介导的分裂引起的突触解离有一个新的认识。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。

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.