TREM2 Drives Microglia Response to Amyloid-β via SYK-dependent and -independent Paths

• Published in: Cell Vol. 185; no. 22; pp. 4153 - 4169.e19
• Main Authors: Wang, Shoutang, Sudan, Raki, Peng, Vincent, Zhou, Yingyue, Du, Siling, Yuede, Carla M., Lei, Tingting, Hou, Jinchao, Cai, Zhangying, Cella, Marina, Nguyen, Khai, Poliani, Pietro L., Beatty, Wandy L., Chen, Yun, Cao, Siyan, Lin, Kent, Rodrigues, Cecilia, Ellebedy, Ali H., Gilfillan, Susan, Brown, Gordon D., Holtzman, David M., Brioschi, Simone, Colonna, Marco
• Format: Journal Article
• Language: English
• Published: 27-10-2022
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2022.09.033

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-GSK3β-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 adaptor 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.
Microglia respond to Aβ through the activation of TREM2 mediated Syk and DAP10 signaling mechanisms. Antibody-mediated activation of Syk in mic expressing the Alzheimer’s disease associated human TREM2R47H allele rescues microglial activation.