CD33调控小胶质细胞功能促进tau病理发生的作用和机制研究

Currently, many large-scale genome-wide association studies (GWAS) have found that CD33 is a novel susceptible gene for AD. In our preliminary studies, we provided the first independent evidence that CD33 loci are associated with the risk of AD in Han Chinese population. Our results were published in Alzheimers Dement. In addition, we found that CD33 risk loci are closely linked to hippocampal atrophy and the level of tau protein in cerebrospinal fluid, implying that they may play an important role in tau pathology. In this subject, we hypothesize that CD33 exacerbates neuronal tau pathology via the modulation of pro-inflammatory responses. At first, we intend to use microglia-neuronal transwell co-culture system, combined with gene knock-out and lentivirus-mediated over-expression technology, to verify the hypothesis that CD33 exacerbates neuronal tau pathology via the modulation of pro-inflammatory responses. Then we intend to figure out the therapeutic effects of targeted CD33 knock-out on tau pathology as well as cognitive deficiency in CD33-/-/hTau transgenic mice and its underlying mechanism. The completion of this project will uncover the role of CD33 in tau pathology under AD context, and will offer novel targets for therapy and drug development of this disease.

目前多个欧美大规模全基因组关联研究发现CD33为AD新的易感基因，本课题组前期亦证实CD33为汉族人群AD的重要易感基因，相关成果发表在《Alzheimers Dement》杂志。此外，我们前期研究发现CD33基因风险位点与海马萎缩和脑脊液tau蛋白水平显著关联，提示其可能参与tau病理发生。在本项目中，我们提出“CD33可能通过调控小胶质细胞促炎功能参与tau病理发生”这一假说并进行验证。首先，我们拟使用Transwell小胶质细胞/神经元共培养系统，结合基因敲除和过表达技术，从细胞水平明确CD33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CD33-/-/hTau转基因小鼠为研究对象，进一步明确靶向敲除CD33对tau病理和相关认知障碍的治疗作用及其潜在机制。本项目的完成不仅可揭示CD33参与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。

目前多个欧美大规模全基因组关联研究发现CD33为AD新的易感基因，本课题组前期亦证实CD33为汉族人群AD的重要易感基因，相关成果发表在《Alzheimers Dement》杂志。在本项目中，我们将ADNI-1,ADNI-GO和ADNI-2中可以获取CD33基因分型的1082名非痴呆人群(包括375名CN和707名MCI患者)纳入分析，探究CD33(rs3826656和rs3865444)与AD关键脑区结构的基线水平体积和四年随访时间内的萎缩率之间的相关性。并探究这种相关性开始于疾病的哪一阶段。结果表明位于CD33基因上的AD易感位点(rs3826656和rs3865444)在痴呆症状出现前阶段可以影响AD关键脑区结构MRI的影像改变。亚组分析的结果表明上述CD33对AD关键脑区结构的影响仅存在于Aβ病理阳性组，而在Aβ病理阴性组中无此相关性，并且这一影响开始于痴呆前期AD阶段。随后我们构建了CD33基因敲除小鼠，利用动物模型进一步探讨了CD33参与AD的潜在的机制。小胶质细胞差异基因富集分析显示CD33基因可能通过MAPK和AGE-RAGE信号通路,直接或间接地参与AD相关的病理生理过程。本项目丰富和完善了AD的发病机制，为AD的药物研发提供全新的靶点和理论依据，因而具有十分重要的科学意义。