脑微出血与认知障碍关系密切，但其机制仍未完全明了。小胶质细胞表型在脑组织病理微环境中有很强异质性，并发挥重要调节作用。单细胞测序发现一种具有全新转录特征的“疾病相关小胶质细胞”（Disease-Associated Microglia，DAM）：细胞膜表面分子Trem2活化是DAM激活的表型特征，其下游信号通路激活能促使DAM准确清除和修复受损髓鞘。我们前期研究表明铁代谢紊乱可导致认知障碍，其主要原因是铁离子改变了小胶质细胞膜表面分子表达和相互作用，但铁离子是否参与调控Trem2的活化及其分子机制目前未知。因此，我们提出如下假说：铁离子过载可能通过抑制Trem2活化，阻碍DAM激活、减弱其对受损髓鞘的清除修复能力，加重脑微出血导致的认知障碍。本项目拟采用体内、外研究，通过多种分子生物学方法，揭示铁离子对DAM表型关键分子Trem2的调控机制，以期深入了解脑微出血认知障碍的发病机制。

Cerebral microbleeds have been closely associated with cognitive impairment, whereas the mechanism remains fully unknown. Microglia, regarded as having heterogeneous phenotypes, plays important regulatory role in the pathological microenvironment of brain tissue. Recent findings with single cell sequencing revealed a type of disease-associated microglia (DAM) with novel transcriptional signature. Trem2 is the key membrane molecule directly linked to activation of DAM, which induces removing debris and repairing damaged myelin. Our previous studies have shown that iron metabolism disorder is associated with cognitive impairment, which is mainly due to the changes of expression and interaction of microglia membrane proteins. However, the influence and iron related mechanism involved in the regulation of Trem2 activation has not been unknown. We propose that iron accumulation may inhibit Trem2 activation, mediating DAM inactivation and inability to repair damaged myelin, which finally results in cognitive impairment in cerebral microbleeds. This study aims to reveal the mechanism that iron regulates the Trem2 activation, the key molecule of DAM phenotype, through animal models and molecular biology experiments, which provides the potential pathogenesis of cognitive impairment in cerebral microbleeds.