Pcdh-γC5介导的神经突触异常参与AD疾病发生的分子机制研究

Synaptic transmission is essential for neuronal communication and signal transduction in nervous system. The abnormality and dysfunction of synaptic transmission has been widely accepted as a causal event in Alzheimer’s disease (AD) and the critical reason for memory loss and cognition deficiency in AD patients. In our previous study, we found that overexpressed cell adhesion molecule Pcdh-γC5 interacted with β-amyloid precursor protein (APP). In addition, the neurotoxic β-amyloid (Aβ) peptide upregulated the expression level of Pcdh-γC5, leading to the dysfunction of synapses. In this current project, we will take advantage of the APP/PS1 transgenic AD mice model and our newly developed Pcdh-γC5 knockout mice, to further investigate the important role as well as the underlying mechanisms of synaptic dysfunction mediated by Pcdh-γC5 in AD pathogenesis. In this project, multiple techniques including coimmunoprecipitation, immunofluorescence, electrophysiological recording and animal behavior test will be used. We hope the proposed study will provide valuable clues in understanding the complex mechanisms of AD pathogenesis and provide potential therapeutic target for AD treatment.

神经突触是神经元之间联系和信号传导的主要方式，突触功能的异常和紊乱是阿尔茨海默病(AD)的一个重要病理特征，也是造成AD病人记忆和认知功能障碍的关键原因。在前期研究中我们发现，过表达的突触粘附蛋白Pcdh-γC5可以与β-淀粉样前体蛋白(APP)相互作用，并且AD疾病的主要致病因素β-淀粉样蛋白(Aβ)可通过上调Pcdh-γC5的表达水平，造成神经元突触功能的异常和紊乱。在本课题中，我们将利用APP/PS1转基因AD模型小鼠和新构建的Pcdh-γC5基因敲除小鼠，采用免疫共沉淀、免疫荧光染色、脑片电生理记录以及动物行为学实验等手段，进一步在整体动物水平研究Pcdh-γC5介导的神经突触功能异常在AD病理中的重要作用，并深入探讨其具体分子机制，希望为阐明AD疾病的发病机理提供有益的线索和潜在诊疗靶点。

神经元的异常兴奋和认知功能障碍是阿尔茨海默症（AD）的重要病理特征，但其具体机制仍未阐明。我们前期报导突触粘附蛋白Pcdh-γC5的表达水平在APP/PS1小鼠皮层和Aβ处理的神经元上均有显著升高。在本课题的研究中，我们进一步揭示Pcdh-γC5在Aβ诱发的神经异常兴奋和认知功能障碍中发挥着关键性的作用。Aβ处理神经元不仅钙依赖性地增加Pcdh-γC5表达水平，而且使突触蛋白水平异常升高。Pcdh-γC5基因敲除则会影响小鼠的突触生成、突触传递及认知功能。采用shRNA特异性敲低APP/PS1小鼠脑中的Pcdh-γC5表达不仅使异常升高的神经元兴奋性恢复正常，并且可以补救APP/PS1小鼠的认知功能障碍。本研究结果表明Pcdh-γC5通过调节突触功能和神经元兴奋性参与AD疾病的病理进程，为AD分子机制的阐明提供了有益的线索，也为AD疾病提供了潜在的治疗靶点。