title: Upregulation of TREM2 ameliorates neuropathology and rescues spatial cognitive impairment in a transgenic mouse model of Alzheimer's disease.
abstract: Triggering receptor expressed on myeloid cells 2 (TREM2) gene is a recently identified susceptibility gene for Alzheimer's disease (AD), as its low-frequency variants increase the risk of this disease with an odds ratio similar to that of an APOE ɛ4 allele. To date, the expression and biologic functions of TREM2 under AD context remain largely unknown. Using APPswe/PS1dE9 mice, a transgenic model of AD, we showed that TREM2 was upregulated in microglia during disease progression. For the first time, we provided in vitro and in vivo evidence that this upregulation was attributed to the increased amyloid-β (Aβ)(1-42) levels in the brain. By knockdown and overexpression of TREM2 in cultured primary microglia, we revealed that TREM2 modulated microglial functions under AD context, as it facilitated Aβ(1-42) phagocytosis and inhibited Aβ(1-42)-triggered proinflammatory responses. Meanwhile, this modulation was dependent on DAP12, the adapter protein of TREM2. More importantly, overexpression of TREM2 in the brain of APPswe/PS1dE9 mice markedly ameliorated AD-related neuropathology including Aβ deposition, neuroinflammation, and neuronal and synaptic losses, which was accompanied by an improvement in spatial cognitive functions. Taken together, our data suggest that the upregulation of TREM2 serves as a compensatory response to Aβ(1-42) and subsequently protects against AD progression by modulation of microglia functions. These findings provide insights into the role of TREM2 in AD pathogenesis, and highlight TREM2 as a potential therapeutic target for this disease.
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Teng
authors.initials: T
authors.lastname: Jiang
authors.affiliation: 1] Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, People's Republic of China [2] Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, People's Republic of China [3] Department of Neurology, Qingdao Municipal Hospital, College of Medicine and Pharmaceutics, Ocean University of China, Qingdao, People's Republic of China.
authors.forename: Lan
authors.initials: L
authors.lastname: Tan
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Xi-Chen
authors.initials: XC
authors.lastname: Zhu
authors.affiliation: The Clinical Laboratory of Nanjing Brain Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Qiao-Quan
authors.initials: QQ
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, College of Medicine and Pharmaceutics, Ocean University of China, Qingdao, People's Republic of China.
authors.forename: Meng-Shan
authors.initials: MS
authors.lastname: Tan
authors.affiliation: Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Li-Ze
authors.initials: LZ
authors.lastname: Gu
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Hui-Fu
authors.initials: HF
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Zheng-Zheng
authors.initials: ZZ
authors.lastname: Ding
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Ying-Dong
authors.initials: YD
authors.lastname: Zhang
authors.affiliation: 1] Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, People's Republic of China [2] Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, People's Republic of China [3] Department of Neurology, Qingdao Municipal Hospital, College of Medicine and Pharmaceutics, Ocean University of China, Qingdao, People's Republic of China [4] Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
authors.forename: Jin-Tai
authors.initials: JT
authors.lastname: Yu
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D057167:Claudins / Q000235:genetics / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D011971:Receptors, Immunologic / Q000378:metabolism*; D013028:Space Perception / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: C491049:Aif1 protein, mouse; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002135:Calcium-Binding Proteins; D057167:Claudins; C492354:Cldn11 protein, mouse; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse; C075222:amyloid beta-protein (1-42)