TREM2调控DAM在1型糖尿病认知功能障碍中作用及其机制

1型糖尿病(T1DM)与认知功能障碍密切相关，严重影响儿童学习和记忆能力，但其发病机制尚不清楚。TREM2是一类与阿尔茨海默病等神经退行性疾病相关的小胶质细胞亚型(DAM)的关键功能蛋白。本课题组前期工作发现，第8和15周T1DM小鼠前额叶皮层TREM2表达显著增加，且可能激活DAM吞噬Aβ寡聚体，提示TREM2可能调控DAM在T1DM认知功能障碍中发挥神经保护作用。据此，本项目拟利用神经科学、细胞生物学、生物化学和分子生物学等学科技术，明确TREM2是激活DAM延缓T1DM认知功能障碍关键分子；阐明TREM2上调T1DM脑内小胶质细胞能量代谢水平，从而激活DAM吞噬Aβ寡聚体；应用代谢组学和生物信息学分析，进一步构建T1DM脑内TREM2激活DAM的关键代谢通路网络。所获成果将揭示TREM2激活DAM的关键代谢分子及机制，为T1DM认知功能障碍防治策略提供新的实验依据。

Type 1 diabetes mellitus (T1DM) is closely related to cognitive impairment which seriously affects children's learning and memory ability, but the pathogenesis is still unclear. TREM2 is a key functional protein of disease-associated microglia (DAM) related to neurodegenerative diseases, such as Alzheimer's disease. In our previous work, we found that the significant increase of TREM2 expression in the prefrontal cortex of T1DM mice at 8 and 15 week might activate DAM to phagocytize Aβ oligomer. Our results suggested that TREM2 might play a neuroprotective role in the T1DM-induced cognitive impairment by activating DAM. Accordingly, this study will firstly explore that TREM2 is the key molecule in DAM activation to delay T1DM-induced cognitive impairment by neuroscience, cell biology, biochemistry, molecular biology and other technologies. Secondly, this study will clarify that TREM2 can up-regulate the energy metabolism of microglia in T1DM brain, thus activating the phagocytosis of Aβ oligomer by DAM. Finally, with the methods of metabolomics and bioinformatics analysis, this study will further construct the key metabolic pathway network of DAM activation by TREM2 in T1DM brain. The results will reveal the key metabolic molecules and mechanisms of DAM activation by TREM2, and provide a new experimental basis for the prevention and treatment strategies of cognitive impairment induced by T1DM.