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

Cell. 2022 Oct 27;185(22):4153-4169.e19. 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 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Brain / metabolism
  • Disease Models, Animal
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Humans
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mice
  • Microglia* / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Plaque, Amyloid / metabolism
  • Receptors, Immunologic / metabolism
  • Syk Kinase / metabolism


  • Glycogen Synthase Kinase 3 beta
  • Phosphatidylinositol 3-Kinases
  • Amyloid beta-Peptides
  • SYK protein, human
  • Syk Kinase
  • TREM2 protein, human
  • Membrane Glycoproteins
  • Receptors, Immunologic
  • Trem2 protein, mouse