title: Dual induction of TREM2 and tolerance-related transcript, Tmem176b, in amyloid transgenic mice: implications for vaccine-based therapies for Alzheimer's disease.
abstract: Vaccine-based autoimmune (anti-amyloid) treatments are currently being examined for their therapeutic potential in Alzheimer's disease. In the present study we examined, in a transgenic model of amyloid pathology, the expression of two molecules previously implicated in decreasing the severity of autoimmune responses: TREM2 (triggering receptor expressed on myeloid cells 2) and the intracellular tolerance-associated transcript, Tmem176b (transmembrane domain protein 176b). In situ hybridization analysis revealed that both molecules were highly expressed in plaque-associated microglia, but their expression defined two different zones of plaque-associated activation. Tmem176b expression was highest in the inner zone of amyloid plaques, whereas TREM2 expression was highest in the outer zone. Induced expression of TREM2 occurred co-incident with detection of thioflavine-S-positive amyloid deposits. Transfection studies revealed that expression of TREM2 correlated negatively with motility, but correlated positively with the ability of microglia to stimulate CD4(+) T-cell proliferation, TNF (tumour necrosis factor) and CCL2 (chemokine ligand 2) production, but not IFNgamma (interferon gamma) production. TREM2 expression also showed a positive correlation with amyloid phagocytosis in unactivated cells. However, activating cells with LPS (lipopolysaccharide), but not IFNgamma, reduced the correlation between TREM2 expression and phagocytosis. Transfection of Tmem176b into both microglial and macrophage cell lines increased apoptosis. Taken together, these data suggest that, in vivo, Tmem176b(+) cells in closest apposition to amyloid may be the least able to clear amyloid. Conversely, the phagocytic TREM2(+) microglia on the plaque outer zones are positioned to capture and present self-antigens to CNS (central nervous system)-infiltrating lymphocytes without promoting pro-inflammatory lymphocyte responses. Instead, plaque-associated TREM2(+) microglia have the potential to evoke neuroprotective immune responses that may serve to support CNS function during pro-inflammatory anti-amyloid immune therapies.
authors.affiliation: Division of Biomedical Sciences, University of California-Riverside, 900 University Avenue, Riverside, CA 92521-0121, U.S.A.
authors.forename: Benoit
authors.initials: B
authors.lastname: Melchior
authors.forename: Angie E
authors.initials: AE
authors.lastname: Garcia
authors.forename: Bor-Kai
authors.initials: BK
authors.lastname: Hsiung
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Lo
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Doose
authors.forename: J Cameron
authors.initials: JC
authors.lastname: Thrash
authors.forename: Anna K
authors.initials: AK
authors.lastname: Stalder
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.forename: Harald
authors.initials: H
authors.lastname: Neumann
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Carson
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control*; D000682:Amyloid / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D016233:Immunotherapy, Active / Q000379:methods; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010587:Phagocytosis / Q000502:physiology; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000235:genetics; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
chemical_list: D000682:Amyloid; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C517262:TREM1 protein, mouse; C498716:Trem2 protein, mouse; D000073871:Triggering Receptor Expressed on Myeloid Cells-1