早老素Presenilin介导的免疫调控及其在神经退行性疾病中的作用

It has been found that inflammation was deeply involved in developing neurodegenerative disease, but the detailed mechanism has not been well illustrated. Our previous study has shown that the expression of the variety of purinergic receptors and inflammatory cytokines was apparently unusual in PS1 and PS2 double knockout mice（dKO） which was regarded as a classic familial Alzheimer disease (FAD) model. Meanwhile, the cognitive deficit was also deteriorated in these mice. These suggested that the defect of presenilin may sensitize the immune system to a hypersensitivity stage. So any faint activation could cause a uncontrollable inflammation which eventually induced neurodegenerative disease, in which process P2X7 play an impotant role in regulation. And it could be a novel Aβ-independent pathogenesis of Alzheimer's disease. Interestingly, this hypothesis was also proven in our preliminary data from PS2 knockout mice. In this project we proposal to further elucidate the function, mechanism and signaling pathway of presenilin in regulation of inflammation-mediated neurodegenerative disease in molecular, cellular and systemic level through dKO mice, PS2 KO mice and PS2 knockdown cells. Furthermore, we will also demonstrate the role and mechanism of P2X7 in inflammation-mediated neurodegenerative disease. Our research will demonstrate the new role of inflammation in the pathogenesis of FAD and lay a foundation for discovering novel anti-AD drugs through a novel way.

神经退行性疾病发生发展与炎症密切相关，但确切机制尚未阐明。本课题前期在家族性阿尔茨海默氏症（FAD）模型即早老素PS1/PS2双基因敲除小鼠（dKO）中，发现其多种嘌呤类受体和炎性因子表达明显异常，并伴随着炎症与认知障碍日趋严重。我们推测PS基因的缺失导致机体处于炎症敏感状态，当存在某种启动因子时就很容易出现炎症反应失控，最终出现FAD症状，在此过程中P2X7发挥着重要的调控作用。这可能是FAD发生的非淀粉样蛋白依赖性的新机制。预实验我们在PS2单基因敲除小鼠中得到了初步的证明。本课题拟继续以dKO小鼠、PS2单基因敲除小鼠/细胞为研究对象，从动物整体、细胞和分子三个层面系统地揭示PS与P2X7之间的相互关系及调控机理，以及P2X7在大脑炎症反应和神经退行性进程中的作用及其信号通路。本课题将从新的视角阐明炎症在FAD中所发挥的关键作用，为药物研发策略提供新的思路。

本项目前期以Presenilin-1/2双基因条件性敲除小鼠（DKO）为动物模型，发现该小鼠除大脑中不形成Aβ42外，表现出多种AD典型的病理症状，尤其是全身性炎症反应等，是研究AD发病机理及治疗方法较好的动物模型。研究发现非甾体类消炎药可以明显改善小鼠因炎症反应而导致的神经退行性症状和外周组织损伤，机理可能是PS基因的缺失明显影响炎症调控分子P2Y6、P2X7等嘌呤类受体的表达。进一步研究发现，PS2单基因缺失的小鼠其P2X7受体明显升高，表现出炎症易感性，当侧脑室注射Aβ时可以引起的神经损伤更为敏感，且与局部大量ATP的释放有关，采用P2X7受体拮抗剂OxATP可以有效抑制这种损伤，因此证明P2X7可能是治疗AD潜在的靶点。另外本研究发现P2Y6、P2X7在巨噬细胞介导的抗细菌、病毒感染以及炎症反应中发挥着重要功能，表现为促细胞因子/趋化因子释放、招募吞噬细胞迁移和促进吞噬等作用。