title: TREM2 modifies microglial phenotype and provides neuroprotection in P301S tau transgenic mice.
abstract: As a novel risk gene for Alzheimer's disease (AD), triggering receptor expressed on myeloid cells 2 (TREM2) gene encodes a type I transmembrane receptor that is uniquely expressed by the microglia in the brain. Emerging evidence indicates a strong association between TREM2 and tau pathology in the cerebral spinal fluid or brain tissue of AD patients. In line with these clinical findings, we found that TREM2 was upregulated in the brain of P301S mice, an animal model of tau pathology, during disease progression. However, despite this information, the precise role of TREM2 in tau pathology remains largely unknown. In our recent studies, we revealed that silencing microglial TREM2 expression in P301S mice exacerbated spatial cognitive deficits and tau pathology. Based on this evidence, we hypothesized that TREM2 might exert a protective effect in tau-related neurodegenerative diseases. In the present study, to test this hypothesis, a lentiviral-mediated strategy was employed to selectively overexpress TREM2 on microglia in the brain of P301S mice. For the first time, we showed that TREM2 overexpression rescued spatial cognitive impairments and ameliorated neuropathologies including neuronal and synaptic loss as well as tau hyperphosphorylation. Meanwhile, this protective effect was likely attributed to the suppression of neuroinflammation and subsequent attenuation of tau kinase activity, since the expression of pro-inflammatory cytokines including Tnf, Il1b and Il6 as well as the activity of tau kinase including glycogen synthase kinase 3β and cyclin-dependent kinase 5 was significantly reduced following TREM2 overexpression. Additionally, the suppressed neuroinflammation might be ascribed to the M2 activation of microglia induced by TREM2, as the expression of M2 phenotype makers including Arg1, Retnla, Il4 and Il10 was markedly increased. Taken together, these findings support the concept of TREM2 as a valuable target against AD as well as other tau-related neurodegenerative diseases.
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China; Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: Teng
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China. Electronic address: zhangyingdong@aliyun.com.
authors.forename: Ying-Dong
authors.initials: YD
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Xi-Chen
authors.initials: XC
authors.lastname: Zhu
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Jun-Shan
authors.initials: JS
authors.lastname: Zhou
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Jian-Quan
authors.initials: JQ
authors.lastname: Shi
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, China; Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China. Electronic address: dr.tanlan@163.com.
authors.forename: Lan
authors.initials: L
authors.lastname: Tan
authors.affiliation: Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA. Electronic address: jintai.yu@ucsf.edu.
authors.forename: Jin-Tai
authors.initials: JT
authors.lastname: Yu
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000523:psychology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000378:metabolism; D005106:Exploratory Behavior / Q000502:physiology; D005822:Genetic Vectors; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D016086:Lentivirus / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D000066829:Neuroprotection; D010641:Phenotype; D010766:Phosphorylation; D011971:Receptors, Immunologic / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D018836:Inflammation Mediators; C558298:Mapt protein, mouse; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse; D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; D000071679:Glycogen Synthase Kinase 3 beta
keywords: Alzheimer's disease; M2 phenotype; Microglia; Neuroinflammation; TREM2; Tau kinase; Tau pathology