TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function

Neuron. 2018 Mar 7;97(5):1023-1031.e7. doi: 10.1016/j.neuron.2018.01.031.


Mutations in triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to increased Alzheimer's disease (AD) risk. Neurobiological functions of TREM2 and its pathophysiological ligands remain elusive. Here we found that TREM2 directly binds to β-amyloid (Aβ) oligomers with nanomolar affinity, whereas AD-associated TREM2 mutations reduce Aβ binding. TREM2 deficiency impairs Aβ degradation in primary microglial culture and mouse brain. Aβ-induced microglial depolarization, K+ inward current induction, cytokine expression and secretion, migration, proliferation, apoptosis, and morphological changes are dependent on TREM2. In addition, TREM2 interaction with its signaling adaptor DAP12 is enhanced by Aβ, regulating downstream phosphorylation of SYK and GSK3β. Our data demonstrate TREM2 as a microglial Aβ receptor transducing physiological and AD-related pathological effects associated with Aβ.

Keywords: Alzheimer’s disease; Aβ; R47H; TREM2; microglia; neuroinflammation.

Publication types

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

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Brain / metabolism*
  • Brain / pathology
  • Cells, Cultured
  • Double-Blind Method
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Microglia / pathology
  • Microglia / physiology*
  • Protein Binding / physiology
  • Receptors, Immunologic / metabolism*


  • Amyloid beta-Peptides
  • Membrane Glycoproteins
  • Receptors, Immunologic
  • Trem2 protein, mouse