Silencing of TREM2 exacerbates tau pathology, neurodegenerative changes, and spatial learning deficits in P301S tau transgenic mice

Neurobiol Aging. 2015 Dec;36(12):3176-3186. doi: 10.1016/j.neurobiolaging.2015.08.019. Epub 2015 Aug 24.


Tau pathology is a pathological hallmark for several neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia. As a novel susceptibility gene for these 2 diseases, triggering receptor expressed on myeloid cells 2 (TREM2) gene encodes an immune receptor that is uniquely expressed by microglia. Recently, a correlation between TREM2 expression and hyperphosphorylated tau has been revealed in the brain of Alzheimer's disease patients, suggesting a potential association between TREM2 and tau pathology. However, the role of TREM2 in tau pathology remains unclear thus far. Herein, using P301S mice, we showed that TREM2 was upregulated in microglia during disease progression. Silencing of brain TREM2 exacerbated tau pathology in P301S mice. This exacerbation might be attributed to neuroinflammation-induced hyperactivation of tau kinases. Additionally, more severe neurodegenerative changes and spatial learning deficits were observed following TREM2 silencing. Our results imply that TREM2 attenuates tau kinase activity through restriction of neuroinflammation, and thus protects against tau pathology. These findings further suggest that TREM2 may represent as a potential therapeutic target for tau-related neurodegenerative diseases.

Keywords: Alzheimer's disease; Frontotemporal dementia; Microglia; Neurodegeneration; Spatial cognitive deficits; TREM2; Tau pathology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Disease Progression*
  • Gene Silencing*
  • Genetic Predisposition to Disease / genetics*
  • Glycogen Synthase Kinase 3 / metabolism
  • Male
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / metabolism
  • Membrane Glycoproteins / physiology*
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia / metabolism
  • Nerve Degeneration*
  • Receptors, Immunologic / genetics*
  • Receptors, Immunologic / metabolism
  • Receptors, Immunologic / physiology*
  • Severity of Illness Index
  • Spatial Learning*
  • Tauopathies / genetics*
  • Tauopathies / pathology*
  • Tauopathies / psychology
  • Up-Regulation


  • Membrane Glycoproteins
  • Receptors, Immunologic
  • Trem2 protein, mouse
  • Glycogen Synthase Kinase 3
  • tau-protein kinase