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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways
Cell, Volume 185, No. 22, Year 2022
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Description
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. © 2022 Elsevier Inc.
Authors & Co-Authors
Poliani, Pietro Luigi
Italy, Brescia
Università Degli Studi Di Brescia
Beatty, Wandy L.
United States, St. Louis
Washington University School of Medicine in St. Louis
Ellebedy, Ali H.
United States, St. Louis
Washington University School of Medicine in St. Louis
Brown, Gordon D.A.
United Kingdom, London
Medical Research Council
Holtzman, David M.
United States, St. Louis
Washington University School of Medicine in St. Louis
Colonna, Marco
United States, St. Louis
Washington University School of Medicine in St. Louis
Statistics
Citations: 77
Authors: 6
Affiliations: 3
Identifiers
Doi:
10.1016/j.cell.2022.09.033
ISSN:
00928674
Research Areas
Cancer
Genetics And Genomics