目前欧美GWAS研究发现IL33为AD新的易感基因，本课题组亦证实IL33为汉族人群AD的重要易感基因。同时，我们前期研究发现AD患者脑脊液IL33水平增高，且与tau蛋白水平显著相关，提示其可能参与tau病理发生。本项目中，我们提出“IL33通过调控小胶质细胞促炎功能，从而延缓tau病理形成”这一假说并进行验证。首先，我们拟使用Transwell培养系统，结合基因敲除技术，从细胞水平明确IL33调控小胶质细胞促炎功能参与tau病理的生物学机制。然后，以ST2-/-/P301S小鼠为研究对象，明确IL-33对tau病理和相关认知障碍的治疗作用。同时，利用AD临床生物样本库，分析体液IL33、sST2水平与老年人群认知功能、脑脊液tau蛋白的相关性，明确其在AD发生中的作用。本项目的完成不仅可揭示IL33参与tau病理的作用机制，更可为AD及其他tau相关疾病的药物研发提供新的靶点。

Currently, genome-wide association studies (GWAS) have found that IL33 is a novel susceptible gene for AD. In our preliminary studies, we provided the first independent evidence that IL33 loci are associated with the risk of AD in Han Chinese population. Meanwhile, our previous studies have found that CSF levels of IL33 were higher in AD patients than those in healthy controls, and were associated with CSF levels of tau protein, implying that they may play an important role in tau pathology. In this subject, we hypothesize that IL33 ameliorates neuronal tau pathology via the modulation of microglial pro-inflammatory responses. At first, we intend to use microglia-neuronal transwell co-culture system and 3D humantriculture system modeling, combined with gene knock-out technology, to verify the hypothesis that IL33 ameliorates neuronal tau pathology via the modulation of pro-inflammatory responses. Besides, using ST2-/-/P301S mice, we intend to study the mechanism of IL33/ST2 pathway in neuronal tau pathology via the modulation of microglial pro-inflammatory responses and the therapeutic effects of IL33 on tau pathology as well as cognitive deficiency. In addition, we intend to analyze the association of CSF and plasma levels of IL33, sST2 with cognitive function and CSF levels of tau protein in elders to further identify the role of IL33/ST2 in AD pathogenesis. The completion of this project will uncover the role of IL33 in tau pathology under AD context, and will offer novel targets for therapy and drug development of this disease.