Cell—小胶质细胞研究重磅突破：TREM2-SYK通路是诱导功能性小胶质细胞的关键！！

中文摘要

遗传学研究表明，小胶质细胞在阿尔茨海默病（AD）的发病中起着关键作用。粘附在Aβ斑块上的小胶质细胞会获得一种转录标记，即“疾病相关小胶质细胞”（DAM），其主要源于通过蛋白酪氨酸激酶SYK传递细胞内信号的TREM2-DAP12受体复合物。与高AD风险相关的人群TREM2 R47H变体不能通过SYK激活小胶质细胞。研究人员发现，SYK缺陷的小胶质细胞无法包裹Aβ斑块，这加速了大脑病理进展和行为缺陷。SYK缺乏损害了PI3K-AKT-GSK-3β-mTOR途径，使获得DAM谱所需的合成代谢支持发生缺陷。然而，SYK缺陷的小胶质细胞增殖并进展到表达Apoe的DAM前驱期；这一途径依赖于与TREM2结合的适配器DAP10。因此，小胶质细胞对Aβ的反应涉及非冗余的SYK-和DAP10途径。使用针对CLEC7A（一种直接激活SYK的受体）的抗体干预TREM2 R47H等位基因的小鼠，可维持小胶质细胞的激活，揭示了AD免疫治疗的新选择。

英文摘要

Genetic studies have highlighted microglia as pivotal in orchestrating Alzheimer's disease (AD). Microglia that adhere to Aβ plaques acquire a transcriptional signature, "disease-associated microglia" (DAM), which largely emanates from the TREM2-DAP12 receptor complex that transmits intracellular signals through the protein tyrosine kinase SYK. The human TREM2R47H variant associated with high AD risk fails to activate microglia via SYK. We found that SYK-deficient microglia cannot encase Aβ plaques, accelerating brain pathology and behavioral deficits. SYK deficiency impaired the PI3K-AKT-GSK-3β-mTOR pathway, incapacitating anabolic support required for attaining the DAM profile. However, SYK-deficient microglia proliferated and advanced to an Apoe-expressing prodromal stage of DAM; this pathway relied on the adapter DAP10, which also binds TREM2. Thus, microglial responses to Aβ involve non-redundant SYK- and DAP10-pathways. Systemic administration of an antibody against CLEC7A, a receptor that directly activates SYK, rescued microglia activation in mice expressing the TREM2R47H allele, unveiling new options for AD immunotherapy.

参考文献：TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways. Cell.2022 Oct 27;185(22):4153-4169.e19. doi: 10.1016/j.cell.2022.09.033.

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