阿尔兹海默病小鼠外周血CD4+ T细胞基因表达及功能变化研究

Neuroinflammation and abnormal changes of immune system occur in the early stages of Alzheimer's disease (AD), but the mechanisms remain unclear. In our previous work, we found that peripheral blood CD4+ T cells expressed APP β-secretase (BACE1) and the proportion of memory CD4+ T cells increased in peripheral blood of AD mice before brain pathological changes take place. This project aims to profile the transcriptome of CD4+ T cells in peripheral blood of APP transgenic mice under different pathological conditions, and analyse the changes of their functions. On this basis, we hope to find out the key genes regulating CD4+ T cell function and clarify its relationship with BACE1 expression and AD pathogenesis. We believe that this research will provide more clues for the pathogenesis of AD, as well as the theoretical basis for immunotherapy of AD.

神经炎症和机体免疫系统的异常变化发生于阿尔兹海默病（AD）的早期阶段，但其作用机制尚不明确。我们在前期工作中发现小鼠外周血CD4+ T细胞表达剪切淀粉样前体蛋白（APP）产生Aβ的重要酶BACE1，并且在尚未发生脑内病理变化情况下AD小鼠外周血记忆性CD4+ T细胞的比例已出现升高。本项目拟通过对不同病理情况下的APP转基因小鼠（APP23）外周血CD4+ T细胞进行转录组测序分析，并分析其功能的变化；在此基础上，寻找调控CD4+ T细胞功能的关键基因，并通过进一步干预，阐明其与BACE1表达和AD发生之间的关系。本项目研究成果将为AD的发病机制提供更多线索，同时为AD的免疫治疗提供理论依据。

免疫系统是人体的防御监测系统，对于维持机体的健康至关重要。衰老过程伴随着机体系统性炎症的增加，长期的慢性炎症导致免疫细胞和分子的异常，进而诱发和加速疾病的发生，因此慢性炎症被认为是导致阿尔茨海默病（Alzheimer's disease，AD）发生发展的重要因素，但其机制尚不明确。本项目探究了在AD发生过程中外周免疫系统CD4+ T细胞的功能异常变化，发现了CD4+ T细胞β-分泌酶（BACE1）分子上调是导致其功能变化的重要因素，并阐述了其中相关的分子信号通路。本项目为进一步探究CD4+ T细胞在AD中的作用及潜在干预策略提供了更多线索。