TREM2 Overexpression has No Improvement on Neuropathology and Cognitive Impairment in Aging APPswe/PS1dE9 Mice

Mol Neurobiol. 2017 Mar;54(2):855-865. doi: 10.1007/s12035-016-9704-x. Epub 2016 Jan 16.

Abstract

Previously, we showed that overexpression of triggering receptor expressed on myeloid cells 2 (TREM2), a microglia-specific immune receptor, in the brain of a middle-aged (7 months old) APPswe/PS1dE9 mice could ameliorate Alzheimer's disease (AD)-related neuropathology by enhancement of microglial amyloid-β (Aβ) phagocytosis. Since AD is an age-related neurodegenerative disorder, it is critical to assess the efficacy of TREM2 overexpression in aging animals with an advanced disease stage. In vivo, we employed a lentiviral strategy to overexpress TREM2 in the brain of aging (18 months old) APPswe/PS1dE9 mice, and observed its efficacy on AD-related neuropathology and cognitive functions. Afterwards, we directly isolated microglia from middle-aged and aging APPswe/PS1dE9 mice and determined effects of TREM2 overexpression on microglial Aβ phagocytosis and Aβ-binding receptors expression in vitro. In aging APPswe/PS1dE9 mice, TREM2 overexpression has no beneficial effect on AD-related neuropathology and spatial cognitive functions. Of note, in vitro experiments showed a significant reduction of Aβ phagocytosis in microglia from aging APPswe/PS1dE9 mice, possibly attributing to the declined expression of Aβ-binding receptors. Meanwhile, this phagocytic deficit in microglia from aging APPswe/PS1dE9 mice cannot be rescued by TREM2 overexpression. Taken together, our study shows that TREM2 overexpression fails to provide neuroprotection in aging APPswe/PS1dE9 mice, possibly attributing to deficits in microglial Aβ phagocytosis at the late-stage of disease progression. These findings indicate that TREM2-mediated protection in AD is at least partially dependent on the reservation of microglial phagocytic functions, emphasizing the importance of early therapeutic interventions for this devastating disease.

Keywords: Aging; Alzheimer’s disease; Amyloid-β; Cognitive impairment; Microglia; Phagocytosis; TREM2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Aging / metabolism*
  • Aging / pathology
  • Amyloid beta-Protein Precursor* / genetics
  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Cognitive Dysfunction / genetics
  • Cognitive Dysfunction / metabolism*
  • Cognitive Dysfunction / pathology
  • Gene Expression
  • Membrane Glycoproteins / biosynthesis*
  • Membrane Glycoproteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Presenilin-1* / genetics
  • Receptors, Immunologic / biosynthesis*
  • Receptors, Immunologic / genetics

Substances

  • Amyloid beta-Protein Precursor
  • Membrane Glycoproteins
  • Presenilin-1
  • Receptors, Immunologic
  • Trem2 protein, mouse