@article{a02bf76093724a05b44fbf1cc7c21205,
title = "TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways",
abstract = "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.",
keywords = "Alzheimer's disease, ApoE, Dectin1, GSK-3β, Syk, TREM2, immunotherapy, metabolism, microglia, signaling",
author = "Shoutang Wang and Raki Sudan and Vincent Peng and Yingyue Zhou and Siling Du and Yuede, {Carla M.} and Tingting Lei and Jinchao Hou and Zhangying Cai and Marina Cella and Khai Nguyen and Poliani, {Pietro L.} and Beatty, {Wandy L.} and Yun Chen and Siyan Cao and Kent Lin and Cecilia Rodrigues and Ellebedy, {Ali H.} and Susan Gilfillan and Brown, {Gordon D.} and Holtzman, {David M.} and Simone Brioschi and Marco Colonna",
note = "Funding Information: This work was supported by the National Institutes of Health (RF1AG05148501, R21 AG059176, and RF1 AG059082, P30AR073752), Cure Alzheimer Fund, and Centene. We thank Richard Cho for generous gift of antibodies and Kooresh I. Shoghi and Chandresh Shyam for pilot experiments. S.W. R.S. Y.Z. S.D. T.L. J.H. Z.C. P.L.P. W.L.B. Y.C. K.L. M. Cella, and S.B. performed in vitro and in vivo studies. V.P. and K.N. analyzed scRNA-seq data. C.M.Y. performed behavioral tests. S.G. prepared some mouse groups. S.W. R.S. Y.Z. Z.C. S.C. and S.B. analyzed data. C.R. G.D.B. and D.M.H. provided critical antibodies. A.H.E. G.D.B. D.M.H. and S.B. provided insightful advice. M. Colonna and S.B. prepared the manuscript with input from S.W. and V.P.M. Colonna conceived and supervised research. M. Colonna is a member of Vigil Neuro scientific advisory board (SAB), is consultant for Cell Signaling Technology and NGM Bio, has received research grants from Vigil Neuro during the conduct of the study, and has a patent to TREM2 pending. DMH co-founded and is on the SAB of C2N Diagnostics; is on the SAB of Denali, Genentech, and Cajal Neuroscience; consults for Alector; and is on the Advisory Board for Cell. Funding Information: This work was supported by the National Institutes of Health ( RF1AG05148501 , R21 AG059176 , and RF1 AG059082 , P30AR073752 ), Cure Alzheimer Fund, and Centene . We thank Richard Cho for generous gift of antibodies and Kooresh I. Shoghi and Chandresh Shyam for pilot experiments. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = oct,
day = "27",
doi = "10.1016/j.cell.2022.09.033",
language = "English",
volume = "185",
pages = "4153--4169.e19",
journal = "Cell",
issn = "0092-8674",
number = "22",
}