人APOE4基因影响AD早期神经元内Aβ42沉积诱导小胶质细胞活化及神经炎症级联反应的分子机制

项目名称： 人APOE4基因影响AD早期神经元内Aβ42沉积诱导小胶质细胞活化及神经炎症级联反应的分子机制

项目编号： No.81471232

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： 赵文娟

作者单位： 上海交通大学

项目金额： 70万元

中文摘要： 阿尔茨海默病（AD）早期神经元内沉积的Aβ42对小胶质细胞的影响或许与细胞外Aβ对小胶质细胞的直接作用有所不同。神经元内Aβ42可能通过CX3CL1－CX3CR1信号系统调节小胶质细胞激活及相关的炎症反应。我们的研究发现APOE4-TR小鼠脑内CX3CR1水平降低；脑内微量注射Aβ1-42 lentivirus 2周后， APOE4-TR小鼠脑内Aβ42免疫阳性小胶质细胞减少而神经元内Aβ42沉积增加。综合分析国内外相关研究，我们的假说认为：APOE4或许通过CX3CL1-CX3CR1信号系统参与Aβ神经元内沉积及小胶质细胞活化，促进神经炎症级联反应。本研究拟应用APOE-TR小鼠与Aβ1-42 lentivirus在细胞及整体动物水平研究APOE4参与小胶质细胞过度活化、诱发神经炎症级联反应的分子机制，希望为AD临床早期诊断/治疗提供潜在的生物标记物及药物靶点。

中文关键词： 载脂蛋白E；小胶质细胞；神经元内Aβ42；CX3CL1；神经炎症

英文摘要： Unlike the direct effect of extracellular β-amyloid (Aβ) on microglia, intraneuronal Aβ42 may affect microglia activation through an alternative pathway. Intraneuronal accumulation of Aβ42 may regulate microglia activation and subsequent neuroinflammation cascade through the CX3CL1 - CX3CR1 signaling system. Our previous study found that CX3CR1 expression was decreased in the brain of APOE4-TR mice. We also found that more neurons with Aβ42 while less microglia with Aβ42 in APOE4-TR mice at 2 weeks after Aβ1-42 lentivirus injection, which revealed that apoE4 tips the balance of the microglial and neuronal Aβ toward the intraneuronal accumulation of Aβ42. Based on the analysis of relevant studies, our hypothesis holds that APOE4 may be involved in intraneuronal accumulation of Aβ, activation of microglia, and promote neuroinflammation cascade through the CX3CL1 - CX3CR1 signaling system. In this study, with the application of APOE-TR mice and Aβ1-42 lentivirus, we plan to clarify the molecular mechanism of human APOE4 genotype affects intraneuronal Aβ42 accumulation induced microglia activation and subsequent neuroinflammation cascade at the early stage of AD, and attempt to find molecules/biomarkers for early diagnosis or therapeutic interventions.

英文关键词： apolipoprotein E;microglia;intraneuronal Aβ42;CX3CL1;neuroinflammation