title: Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer's Disease.
abstract: Neuroinflammation is an important contributor to Alzheimer's disease (AD) pathogenesis, as underscored by the recent identification of immune-related genetic risk factors for AD, including coding variants in the gene TREM2 (triggering receptor expressed on myeloid cells 2). Understanding TREM2 function promises to provide important insights into how neuroinflammation contributes to AD pathology. However, studies so far have produced seemingly conflicting results, with reports that amyloid pathology can be both decreased and increased in TREM2-deficient AD mouse models. In this study, we unify these previous findings by demonstrating that TREM2 deficiency ameliorates amyloid pathology early, but exacerbates it late in disease progression in the APPPS1-21 mouse model of AD. We also demonstrate that TREM2 deficiency decreases plaque-associated myeloid cell accumulation by reducing cell proliferation, specifically late in pathology. In addition, TREM2 deficiency reduces myeloid cell internalization of amyloid throughout pathology, but decreases inflammation-related gene transcript levels selectively late in disease progression. Together, these results suggest that TREM2 plays distinct functional roles at different stages in AD pathology.
  
  
  
  Alzheimer's disease (AD) is a devastating neurodegenerative disorder and there are currently no effective treatments that modify disease progression. However, the recent identification of genetic risk factors for AD promises to provide new insight into AD biology and possible new therapeutic targets. Among these risk factors, variants in the gene TREM2 (triggering receptor expressed on myeloid cells 2) confer greatly elevated risk for developing the disease. We demonstrate that TREM2 deficiency has opposing effects on AD-related pathologies at early and late stages of disease progression, unifying previous work in the field. In addition, we examine how TREM2 affects the function of the brain immune cell populations in which it is expressed throughout disease progression to understand possible mechanisms underlying its differential impacts on pathology.
authors.affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106.|Department of Neurosciences, The Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195.
authors.forename: Taylor R
authors.initials: TR
authors.lastname: Jay
authors.affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Anna M
authors.identifier: 0000-0001-6740-4374
authors.initials: AM
authors.lastname: Hirsch
authors.affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Margaret L
authors.identifier: 0000-0001-6997-7897
authors.initials: ML
authors.lastname: Broihier
authors.affiliation: Department of Neurosciences, The Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195.
authors.forename: Crystal M
authors.identifier: 0000-0002-5074-6914
authors.initials: CM
authors.lastname: Miller
authors.affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Lee E
authors.identifier: 0000-0002-1866-0344
authors.initials: LE
authors.lastname: Neilson
authors.affiliation: Neuroimmunology/Discovery Biology, Biogen, Cambridge, Massachusetts 02142, and.
authors.forename: Richard M
authors.identifier: 0000-0003-0175-6910
authors.initials: RM
authors.lastname: Ransohoff
authors.affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106.|Stark Neurosciences Research Institute, Indiana University, Indianapolis, Indiana 46202.
authors.forename: Bruce T
authors.identifier: 0000-0001-8507-2561
authors.initials: BT
authors.lastname: Lamb
authors.affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106, gel2@case.edu.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Landreth
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D011971:Receptors, Immunologic / Q000172:deficiency* / Q000235:genetics
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse
keywords: AD; genetic risk factor; inflammation; microglia; myeloid cell; neuroinflammation