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

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.

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。

本项目研究关注阿尔茨海默病（Alzheimer’s Disease，AD）发病早期关键时间窗及高风险因素，探讨疾病早期AD发生相关的关键分子的特定改变及其参与AD发病的分子机制。在本项目的资助下，我们的研究发现，AD早期神经元内Aβ42积聚通过影响神经元与小胶质细胞之间CX3CL1-CX3CR1信号通路调节小胶质细胞活化与炎症反应；apoE参与HSV-1诱导的自噬，apoE4促进HSV-Ⅰ在脑内诱导的自噬、Aβ积聚及学习记忆障碍等AD病理和行为学改变；AD高风险因素APOE4等位基因、年龄及性别三者共同影响APOE4-TR小鼠脑内IgG水平及Aβ沉积，MHCⅡ参与的小胶质细胞活化异常可能与10月龄雌性APOE4-TR小鼠脑内Aβ沉积有关。这些研究结果有助于我们更深入地了解AD的发病机制；AD发生早期的关键分子/生物标记物如Aβ42、apoE4、CX3CL1、CX3CR1、IgG等也是AD临床早期诊断/防治的潜在靶点。