The triggering receptor expressed on myeloid cells 2 (TREM2) is associated with enhanced inflammation, neuropathological lesions and increased risk for Alzheimer's dementia

Alzheimers Dement. 2015 Oct;11(10):1163-70. doi: 10.1016/j.jalz.2014.10.013. Epub 2014 Dec 9.

Abstract

Introduction: The objective of this study was to elucidate the relationship between the triggering receptor expressed on myeloid cells 2 (TREM2) risk variant, neuropathological lesions, alterations in gene and protein expression, and the severity of neuroinflammation.

Methods: The genetic association study of the R47 H TREM2 variant with Alzheimer's disease (AD), neuropathology, and changes in TREM2 and TYRO protein tyrosine kinase-binding protein (TYROBP) gene and protein expression, and neuroinflammatory markers.

Results: The TREM2 variant is associated with: (i) AD (odds ratio: 4.76; P = .014); (ii) increased density of amyloid plaques and neurofibrillary tangles in multiple brain regions; (iii) increased TREM2 (P = .041) and TYROBP (P = .006) gene expression; (iv) decreased TREM2 protein levels (P = .016); and (v) upregulation of proinflammatory cytokines (regulated on activation, normal T cell expressed and secreted [RANTES] and interferon [IFN] gamma) (P = .003) and nominal downregulation of protective markers (α2-macroglobulin, interleukin 4 or IL-4, and ApoA1) (P = .018).

Discussion: These findings link the TREM2 missense mutation with specific molecular abnormalities and increases in neuropathological lesions in the human brain.

Keywords: Gene expression; Inflammation; Microglia; Mutation; Protein; TYROBP.

Publication types

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

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology
  • Apolipoprotein E4 / genetics
  • Brain / pathology*
  • Case-Control Studies
  • Female
  • Gene Expression
  • Genetic Association Studies
  • Humans
  • Inflammation / genetics*
  • Inflammation / metabolism
  • Interleukin-4 / metabolism
  • Membrane Glycoproteins / genetics*
  • Mutation, Missense*
  • Myeloid Cells
  • Plaque, Amyloid / pathology
  • Receptors, Immunologic / genetics*
  • Risk

Substances

  • Apolipoprotein E4
  • IL4 protein, human
  • Membrane Glycoproteins
  • Receptors, Immunologic
  • TREM2 protein, human
  • Interleukin-4