Activation of FAK/Rac1/Cdc42-GTPase signaling ameliorates impaired microglial migration response to Aβ42 in triggering receptor expressed on myeloid cells 2 loss-of-function murine models

FASEB J. 2020 Aug;34(8):10984-10997. doi: 10.1096/fj.202000550RR. Epub 2020 Jul 1.


Mutation of Triggering receptor expressed on myeloid cells 2 (TREM2) impairs the response of microglia to amyloid-β (Aβ) pathology in Alzheimer's disease (AD), although the mechanism governing TREM2-regulated microglia recruitment to Aβ plaques remains unresolved. Here, we confirm that TREM2 mutation attenuates microglial migration. Then, using Trem2-/- mice and an R47H variant mouse model for AD generated for this study, we show that TREM2 deficiency or the AD-associated R47H mutation results in inhibition of FAK and Rac1/Cdc42-GTPase signaling critical for cell migration. Intriguingly, treatment with CN04, a Rac1/Cdc42-GTPase activator, partially enhances microglial migration in response to oligomeric Aβ42 in Trem2-/- or R47H microglia both in vitro and in vivo. Our study shows that the dysfunction of microglial migration in the AD-associated TREM2 R47H variant is caused by FAK/Rac1/Cdc42 signaling disruption, and that activation of this signaling ameliorates impaired microglial migration response to Aβ42 , suggesting a therapeutic target for R47H-bearing patients with high risk of AD.

Keywords: Alzheimer's disease; FAK/Rac1/Cdc42 pathway; TREM2; microglia; migration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / genetics*
  • Animals
  • Brain / pathology
  • Cell Movement / genetics*
  • Cells, Cultured
  • Disease Models, Animal
  • Focal Adhesion Kinase 1 / genetics*
  • GTP Phosphohydrolases / genetics*
  • Loss of Function Mutation / genetics
  • Male
  • Membrane Glycoproteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / metabolism
  • Microglia / pathology*
  • Myeloid Cells / metabolism*
  • Myeloid Cells / pathology
  • Neuropeptides / genetics*
  • Peptide Fragments / genetics*
  • Signal Transduction / genetics
  • cdc42 GTP-Binding Protein / genetics*
  • rac1 GTP-Binding Protein / genetics*


  • Amyloid beta-Peptides
  • Cdc42 protein, mouse
  • Membrane Glycoproteins
  • Neuropeptides
  • Peptide Fragments
  • Rac1 protein, mouse
  • amyloid beta-protein (1-42)
  • Focal Adhesion Kinase 1
  • Ptk2 protein, mouse
  • GTP Phosphohydrolases
  • cdc42 GTP-Binding Protein
  • rac1 GTP-Binding Protein