Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology

Neuron. 2021 Apr 21;109(8):1283-1301.e6. doi: 10.1016/j.neuron.2021.02.010. Epub 2021 Mar 5.


Loss-of-function TREM2 mutations strongly increase Alzheimer's disease (AD) risk. Trem2 deletion has revealed protective Trem2 functions in preclinical models of β-amyloidosis, a prominent feature of pre-diagnosis AD stages. How TREM2 influences later AD stages characterized by tau-mediated neurodegeneration is unclear. To understand Trem2 function in the context of both β-amyloid and tau pathologies, we examined Trem2 deficiency in the pR5-183 mouse model expressing mutant tau alone or in TauPS2APP mice, in which β-amyloid pathology exacerbates tau pathology and neurodegeneration. Single-cell RNA sequencing in these models revealed robust disease-associated microglia (DAM) activation in TauPS2APP mice that was amyloid-dependent and Trem2-dependent. In the presence of β-amyloid pathology, Trem2 deletion further exacerbated tau accumulation and spreading and promoted brain atrophy. Without β-amyloid pathology, Trem2 deletion did not affect these processes. Therefore, TREM2 may slow AD progression and reduce tau-driven neurodegeneration by restricting the degree to which β-amyloid facilitates the spreading of pathogenic tau.

Keywords: Alzheimer’s disease; MRI; TREM2; disease-associated microglia; gliosis; microglia; neurodegeneration; neuroinflammation; single-cell RNA sequencing; tauopathy.

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid / metabolism*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Atrophy / genetics
  • Atrophy / metabolism
  • Atrophy / pathology
  • Brain / metabolism*
  • Brain / pathology
  • Disease Models, Animal
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Transgenic
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • tau Proteins / genetics
  • tau Proteins / metabolism*


  • Amyloid
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Membrane Glycoproteins
  • Receptors, Immunologic
  • Trem2 protein, mouse
  • tau Proteins