The role of TREM2 in Alzheimer's disease; evidence from transgenic mouse models

Neurobiol Aging. 2020 Feb;86:39-53. doi: 10.1016/j.neurobiolaging.2019.09.004. Epub 2019 Sep 23.

Abstract

Alzheimer's disease (AD) is a currently incurable neurodegenerative disorder. Several genetic studies have identified a rare variant of triggering receptor expressed on myeloid cells 2 (TREM2) as a risk factor for AD. TREM2 is thought to trigger the microglial response to amyloid plaques. Mouse models have helped elucidate mechanisms through which TREM2 affects microglial function and modulates pathological features of AD. A synthesis of the 35 mouse-model studies included in this review indicates that TREM2 modulates amyloid plaque composition and deposition, microglial morphology and proliferation, neuroinflammation, and tau phosphorylation. TREM2 also acts as a sensor for anionic lipids exposed during neuronal apoptosis and Aβ deposition, may improve spatial abilities and memory, and protect against apoptosis. In early stages of AD, TREM2 knock-down reduces expression of proinflammatory cytokines and upregulates anti-inflammatory cytokines but in later stages, TREM2 may contribute to the disease by aggravating neuroinflammation. The results provide insight into TREM2-related mechanisms that may be associated with AD in humans and may aid future development of disease-modifying pharmacological treatments targeting TREM2.

Keywords: Alzheimer's disease; Amyloid beta; Inflammation; TREM2; Transgenic mouse model.

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Cell Proliferation
  • Cytokines / metabolism
  • Disease Models, Animal
  • Humans
  • Inflammation
  • Inflammation Mediators / metabolism
  • Membrane Glycoproteins / physiology*
  • Mice, Transgenic
  • Microglia / pathology
  • Microglia / physiology
  • Molecular Targeted Therapy
  • Phosphorylation
  • Receptors, Immunologic / physiology*
  • Risk
  • tau Proteins / metabolism

Substances

  • Amyloid beta-Peptides
  • Cytokines
  • Inflammation Mediators
  • Membrane Glycoproteins
  • Receptors, Immunologic
  • Trem2 protein, mouse
  • tau Proteins