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 TREM2^R47H 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 TREM2^R47H allele, unveiling new options for AD immunotherapy.

遗传学研究强调小胶质细胞在阿尔茨海默病 (AD) 中发挥着关键作用。粘附在 Aβ 斑块上的小胶质细胞获得转录特征，即“疾病相关小胶质细胞”(DAM)，它主要源自 TREM2-DAP12 受体复合物，该复合物通过蛋白酪氨酸激酶 SYK 传递细胞内信号。与高 AD 风险相关的人类TREM2 ^R47H变体无法通过 SYK 激活小胶质细胞。我们发现 SYK 缺陷的小胶质细胞无法包裹 Aβ 斑块，从而加速大脑病理和行为缺陷。SYK 缺陷会损害 PI3K-AKT-GSK-3β-mTOR 通路，从而无法实现 DAM 特征所需的合成代谢支持。然而，SYK 缺陷的小胶质细胞增殖并进展至DAM 表达Apoe的前驱阶段；该途径依赖于接头 DAP10，它也结合 TREM2。因此，小胶质细胞对 Aβ 的反应涉及非冗余 SYK 和 DAP10 途径。全身施用针对 CLEC7A（一种直接激活 SYK 的受体）的抗体，可以挽救表达TREM2 ^R47H等位基因的小鼠中的小胶质细胞激活，从而为 AD 免疫治疗提供了新的选择。