title: TREM2 Promotes Microglial Survival by Activating Wnt/β-Catenin Pathway.
abstract: Triggering Receptor Expressed on Myeloid cells 2 (TREM2), which is expressed on myeloid cells including microglia in the CNS, has recently been identified as a risk factor for Alzheimer's disease (AD). TREM2 transmits intracellular signals through its transmembrane binding partner DNAX-activating protein 12 (DAP12). Homozygous mutations inactivating TREM2 or DAP12 lead to Nasu-Hakola disease; however, how AD risk-conferring variants increase AD risk is not clear. To elucidate the signaling pathways underlying reduced TREM2 expression or loss of function in microglia, we respectively knocked down and knocked out the expression of TREM2 inin vitroandin vivomodels. We found that TREM2 deficiency reduced the viability and proliferation of primary microglia, reduced microgliosis inTrem2-/-mouse brains, induced cell cycle arrest at the G1/S checkpoint, and decreased the stability of β-catenin, a key component of the canonical Wnt signaling pathway responsible for maintaining many biological processes, including cell survival. TREM2 stabilized β-catenin by inhibiting its degradation via the Akt/GSK3β signaling pathway. More importantly, treatment with Wnt3a, LiCl, or TDZD-8, which activates the β-catenin-mediated Wnt signaling pathway, rescued microglia survival and microgliosis inTrem2-/-microglia and/or inTrem2-/-mouse brain. Together, our studies demonstrate a critical role of TREM2-mediated Wnt/β-catenin pathway in microglial viability and suggest that modulating this pathway therapeutically may help to combat the impaired microglial survival and microgliosis associated with AD.SIGNIFICANCE STATEMENTMutations in theTREM2(Triggering Receptor Expressed on Myeloid cells 2) gene are associated with increased risk for Alzheimer's disease (AD) with effective sizes comparable to that of the apolipoprotein E (APOE) ε4 allele, making it imperative to understand the molecular pathway(s) underlying TREM2 function in microglia. Our findings shed new light on the relationship between TREM2/DNAX-activating protein 12 (DAP12) signaling and Wnt/β-catenin signaling and provide clues as to how reduced TREM2 function might impair microglial survival in AD pathogenesis. We demonstrate that TREM2 promotes microglial survival by activating the Wnt/β-catenin signaling pathway and that it is possible to restore Wnt/β-catenin signaling when TREM2 activity is disrupted or reduced. Therefore, we demonstrate the potential for manipulating the TREM2/β-catenin signaling pathway for the treatment of AD.
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China, bu.guojun@mayo.edu honghua@xmu.edu.cn.
authors.forename: Honghua
authors.identifier: 0000-0001-7589-2646
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China.|Department of Neuroscience and.
authors.forename: Lin
authors.initials: L
authors.lastname: Jia
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China.|Department of Neuroscience and.
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China.
authors.forename: Zhouyi
authors.identifier: 0000-0003-4849-1278
authors.initials: Z
authors.lastname: Rong
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhong
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China.
authors.forename: Longyu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China.
authors.forename: Xiao-Fen
authors.initials: XF
authors.lastname: Chen
authors.affiliation: Department of Neuroscience and.|Neurobiology of Disease Graduate Program, Mayo Clinic, Jacksonville, Florida 32224, and.
authors.forename: John D
authors.initials: JD
authors.lastname: Fryer
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China.
authors.forename: Xin
authors.identifier: 0000-0003-2421-4639
authors.initials: X
authors.lastname: Wang
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China.|Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037.
authors.forename: Yun-Wu
authors.initials: YW
authors.lastname: Zhang
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China.|Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037.
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China, bu.guojun@mayo.edu honghua@xmu.edu.cn.|Department of Neuroscience and.|Neurobiology of Disease Graduate Program, Mayo Clinic, Jacksonville, Florida 32224, and.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007608:Kainic Acid / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D013830:Thiadiazoles / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D000276:Adjuvants, Immunologic; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D013830:Thiadiazoles; C498716:Trem2 protein, mouse; D051176:beta Catenin; D019938:Cyclin D1; D053148:Caspase 3; D018021:Lithium Chloride; D007608:Kainic Acid
keywords: Akt/GSK3β signaling pathway; Alzheimer's disease; TREM2; Wnt/β-catenin signaling pathway; cell survival; microglia