早期阿尔茨海默病中β淀粉样蛋白影响在体海马长时程抑制的机制

项目名称： 早期阿尔茨海默病中β淀粉样蛋白影响在体海马长时程抑制的机制

项目编号： No.81471114

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 胡能伟

作者单位： 皖南医学院

项目金额： 70万元

中文摘要： 阿尔茨海默病（AD）中ß淀粉样蛋白（Aß）导致易感脑区的突触功能障碍可能是早期AD的主要发病机制。目前Aß干扰突触传递可塑性变化的研究主要集中在NMDA受体依赖的长时程增强（LTP）和长时程抑制（LTD），而对非NMDA受体依赖的突触传递可塑性则知之甚少。我们在最近的研究中于麻醉大鼠海马区成功诱导出mAChR依赖的LTD，侧脑室注射Aß可易化出海马mGlu5R依赖的LTD。然而，这两种LTD的功能和详细细胞分子机制还不清楚；而脑内Aß水平长时间异常增高对mAChR-LTD的影响尚需进一步研究。本项目将在急性、慢性及APP转基因大鼠模型上，运用电生理、行为学测试、免疫组织化学和分子生物学等多种手段重点研究Aß易化的在体海马mGlu5R-LTD的机制，揭示早期AD突触传递可塑性变化障碍的新机制，从而为了解AD的发病机制及寻找有效治疗靶点提供新的方向。

中文关键词： 阿尔茨海默病；β淀粉样蛋白；长时程抑制；海马

英文摘要： Amyloid-? protein (A?), especially the soluble A? oligomers, can potentially disrupt synaptic mechanism in vulnerable brain regions and this synaptic disruption may be the primary cause of early AD. Although numerous reports show A?-mediated disruption effects on long-term potentiation (LTP) and long-term depression (LTD) that require NMDARs, only a few studies have investigated the effects on forms of synaptic plasticity that do not require NMDARs. Our very recent result shows that soluble A? usurp endogenous acetylcholine muscarinic receptor (mAChR)-dependent LTD, to enable LTD that required metabotropic glutamate 5 receptors (mGlu5R).It is still unclear if long-term aberrant high level of A? will cause diffent changes to LTD. The functional roles of these two kinds of LTD and their molecular mechanisms remain to be elucidated. In this project, we will use a multifaceted approach including electrophysiology, behavioral assays and immunohistochemistry and molecular biology in the acute anesthetized, chronic awake and APP transgenic rats. The results of these studies are expected to discover new mechanisms of synaptic disruption in early AD, thus providing a novel therapeutic target for the treatment of AD.

英文关键词： Alzheimer's disease;amyloid-β protein;long-term depression;hippocampus