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The triggering receptor expressed on myeloid cells 2 ( TREM2 ) is associated with enhanced inflammation, neuropathological lesions and increased risk for Alzheimer's dementia
Author(s) -
Roussos Panos,
Katsel Pavel,
Fam Peter,
Tan Weilun,
Purohit Dushyant P.,
Haroutunian Vahram
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2014.10.013
Subject(s) - trem2 , proinflammatory cytokine , neuroinflammation , gas6 , downregulation and upregulation , biology , neuropathology , inflammation , immunology , receptor , microglia , medicine , pathology , gene , disease , receptor tyrosine kinase , genetics
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.