ox-LDL激活巨噬细胞释放外泌体促进Aβ播散及神经炎症的机制研究

临床表明，血管性因素加速了脑内Aβ的聚集和传播，然而机制不明。在动脉硬化进程中，ox-LDL激活的巨噬细胞发挥了重要病理作用。我们研究提示外周ox-LDL激活的巨噬细胞可以通过外泌体促进海马神经元内Aβ的代谢和聚集，并加重病变局部的炎症反应。本课题将首先探讨巨噬细胞外泌体进入中枢的可能性及机制；继而从巨噬细胞外泌体介导LncRNA BACE-AS与神经元BACE1 mRNA相互作用出发，探索巨噬细胞外泌体加速神经元Aβ生成的机制；最后论证巨噬细胞外泌体对与其同源的小胶质细胞M1/M2表型转化的影响，探索其促进神经炎症和含Aβ的外泌体“种子”在脑内传播的机制。本课题拟采用多种体内/外模型结合分子生物学探索在管壁损伤因素ox-LDL作用下，外周活化巨噬细胞是否有可能对中枢神经炎症和变性产生影响，并探讨分子机制，为明确神经变性疾病中血管和变性因素的相互作用关系提供理论基础。

Clinical evidence showed that vascular risk factors promote the aggregation and spreading of Aβ, while the mechanisms are still unclear. ox-LDL activated macrophage plays an important role in arteriosclerosis. Our previous data showed that exosomes from ox-LDL activated macrophage increased the aggregation and transmission of neuronal Aβ and neuroinflammation in the brain. First, this study aims to explore how do exosomes from ox-LDL activated macrophage enter brain. Next, this study focuses on the interaction between LncRNA BACE-AS and BACE1 mRNA which localized in neurons mediated by macrophage-derived exosomes, and also the metabolism of Aβ. Due to the same origin of microglia and macrophage, this study also aims to demonstrate the influence of macrophage-derived exosomes on the M1/M2 phenotype of microglia, which in turn, promoting or suppressing the spreading of neuronal exosomes and Aβ pathology. To verify this hypothesis, several in vivo and in vitro models combined with molecular biology, electrophysiology, and other techniques were used to explore the specific molecular mechanism of neuronal Aβ pathology mediated by macrophage-derived exosomes through LncRNA BACE-AS. The pathogenesis of vascular cognitive impairment is explained from the new perspective of macrophage derived exosomes mediating the interaction between microglia and neuron.