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

• Published in: Alzheimer's & dementia Vol. 11; no. 10; pp. 1163 - 1170
• Main Authors: Roussos, Panos, Katsel, Pavel, Fam, Peter, Tan, Weilun, Purohit, Dushyant P, Haroutunian, Vahram
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2015
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - pathology; Apolipoprotein E4 - genetics; Brain - pathology; Case-Control Studies; Female; Gene Expression; Genetic Association Studies; Humans; Inflammation; Inflammation - genetics; Inflammation - metabolism; Interleukin-4 - metabolism; Membrane Glycoproteins - genetics; Microglia; Mutation; Mutation, Missense; Myeloid Cells; Neurology; Plaque, Amyloid - pathology; Protein; Receptors, Immunologic - genetics; Risk; TYROBP; Inflammation; TYROBP; Mutation; Gene expression; Protein; Microglia
• ISSN: 1552-5260; 1552-5279
• DOI: 10.1016/j.jalz.2014.10.013

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.