神经元细胞内Aβ对GluR2-N-cadherin信号通路调控机制的研究

β样淀粉蛋白（Aβ）的代谢异常长期以来一直被认为是阿尔茨海默症（AD）的重要致病机理之一。它可以使突触传递发生缺陷、改变树突棘等重要功能性结构，最终导致大量神经元的死亡。相关研究目前主要集中在细胞外的Aβ沉积及脑脊液中可溶性Aβ寡聚体对神经元的毒性作用，而对神经元细胞内Aβ42致病机理的探讨则非常有限。有证据显示细胞内Aβ42不仅在病理条件下是AD的一个关键致病因素，在正常生理条件下对神经元功能的调节也是必要的。代谢性谷氨酸受体依赖型长时程抑制（mGluR-LTD）是一个重要的突触可塑性模型，现已知它可以通过GluR2-N-cadherin信号通路同时调控突触传递及树突棘形态。本课题采用电生理、免疫荧光成像及生化分析为主要研究手段，就神经元细胞内Aβ42对此通路的影响展开研究，试图阐明细胞内Aβ42在生理和病理条件下通过此信号通路以调节神经元功能的分子机制。

β-amyloid (Aβ) is one of the crucial pathological determinant of Alzheimer's disease (AD). Its deleterious effects on cortical neurons include deficits of synaptic plasticity and altered spine morphology. Previous studies focused mainly on extracellular Aβ deposition and soluble oligomers. However, intraneuronal Aβ42 has been shown to be an important regulator of neuronal functions under both physiological and pathological conditions, but its role in the etiology of AD remains largely unknown. Metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) is a major model of synaptic plasticity. It is recently reported to simultaneously regulate synaptic transmission and spine morphology through a signaling pathway mediated by GluR-N-cadherin interaction. Using a combination of techniques, including electrophysiological recording, immunostaining and biochemical assays, this study will examine the effects of intraneuronal Aβ42 on GluR2-N-cadherin pathway. We will first investigate the physiological functions of intraneuronal Aβ42, then test its pathological role in AD. This project aims to elucidate the underlying molecular mechanisms of intracellular Aβ42 on neuronal functions.