DISC1介导的慢性炎症反应在AD发病中的作用及其机制研究

Chronic inflammatory response is one of the key reasons for the progression of AD pathology, but its mechanism reminds unknown. Mitophagy-mediated clearance of inflammasome plays an important role in the development of inflammation. Our previous study found that DISC1 can activate mitophagy and down-regulate NLRP3 inflammasome, while reducing microglia infiltration. Moreover, DISC1 is lowly expressed in AD mice and human brain. Combined with the literature and previous results, we propose that DISC1 activates mitophagy to clear NLRP3 inflammatory bodies and inhibit chronic inflammatory response in AD, which improves the progression of AD pathology. This project intends to use primary cell culture and transgenic animal models to clarify that: 1) the role of DISC1 in the chronic inflammation of AD; 2) the effects of mitophagy induced by DISC1 on NLRP3 inflammasome in microglia as well as DISC1-mediated inflammation in Aβ production and tau protein metabolism; 3) DISC1 as a biological marker of AD for the diagnosis of early AD. This study not only enriches the understanding of the pathogenesis of AD, but also provides a new target for the treatment of AD. It is also expected to provide experimental evidence for DISC1 as a biomarker for early diagnosis of AD.

慢性炎症反应是AD病理进展的关键原因之一，但其机制未明。线粒体自噬介导的炎性小体的清除在炎症的发生发展中扮演重要角色。我们的前期研究发现，DISC1能激活线粒体自噬、下调NLRP3炎性小体、减轻小胶质细胞浸润；DISC1在AD小鼠和人脑中低表达。结合文献及前期结果，我们提出：DISC1激活线粒体自噬清除NLRP3炎性小体抑制AD中的慢性炎症反应，延缓AD病理进展。本项目拟利用原代细胞培养和转基因动物模型阐明：1）DISC1在AD慢性炎症反中的调控作用；2）DISC1引起的线粒体自噬对小胶质细胞中NLRP3炎性小体的调控作用及DISC1介导的炎症在Aβ的生成和tau蛋白代谢中的作用机制；3）DISC1作为AD生物学标记物对诊断早期AD的指导意义。该研究不仅可以丰富对AD发病机制的认识，为AD的治疗提供新的靶点，也有望提供DISC1作为AD早期诊断的生物标记物的实验证据。

慢性炎症反应是AD病理进展的关键原因之一，但其机制未明。线粒体自噬介导的炎性小体的清除在炎症的发生发展中扮演重要角色。本项目拟阐明DISC1作为线粒体自噬受体是怎样通过调控小胶质细胞中的线粒体自噬从而调控其炎症反应来改善AD的病理进程。本项目利用用原代小胶质细胞及神经元细胞培养、AD转基因动物模型阐明了：1）DISC1能够激活小胶质细胞的线粒体自噬并减轻Aβ引起的小胶质细胞的炎症反应，从而起到对神经元的保护作用 ；同样的，DISC1能够减轻AD小鼠脑中小胶质细胞的浸润及神经炎症的激活 2）DISC1通过下调小胶质细胞中的NLRP3炎症小体的激活来减轻AD中的炎症反应 3）DISC1通过下调小胶质细胞中的NLRP3炎症小体的激活来减轻AD中的炎症反应是线粒体自噬依赖的，即突变的DISC1（不能激活线粒体自噬）不能减轻AD中的NLRP3小体的激活 4）DISC1在人脑样本中低表达。该研究不仅可以丰富对AD发病机制的认识，为AD的治疗提供新的靶点，也有望提供DISC1作为AD诊断的生物标记物的实验证据。