TREM2 drives microglia response to amyloid-b via SYK-dependent and-independent pathways

Genetic studies have highlighted microglia as pivotal in orchestrating Alzheimer's disease (AD). Microglia that adhere to Ab 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 mi-croglia via SYK. We found that SYK-deficient microglia cannot encase Ab plaques, accelerating brain pathol-ogy and behavioral deficits. SYK deficiency impaired the PI3K-AKT-GSK-3b-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 Ab involve non-redundant SYK-and DAP10-pathways. Sys-temic administration of an antibody against CLEC7A, a receptor that directly activates SYK, rescued micro-glia activation in mice expressing the TREM2R47H allele, unveiling new options for AD immunotherapy.