{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T22:54:09Z","timestamp":1790722449534,"version":"4.1.0"},"reference-count":48,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2016,6,1]],"date-time":"2016-06-01T00:00:00Z","timestamp":1464739200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"}],"funder":[{"DOI":"10.13039\/501100000829","name":"Education Department","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000829","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01AG027924"],"award-info":[{"award-number":["R01AG027924"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01AG035355"],"award-info":[{"award-number":["R01AG035355"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01AG046205"],"award-info":[{"award-number":["R01AG046205"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation","doi-asserted-by":"crossref","award":["81100842"],"award-info":[{"award-number":["81100842"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation","doi-asserted-by":"crossref","award":["U1505227"],"award-info":[{"award-number":["U1505227"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["clinicalkey.jp","clinicalkey.com","clinicalkey.es","clinicalkey.fr","clinicalkey.com.au","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Neurobiology of Aging"],"published-print":{"date-parts":[[2016,6]]},"DOI":"10.1016\/j.neurobiolaging.2016.03.004","type":"journal-article","created":{"date-parts":[[2016,3,15]],"date-time":"2016-03-15T22:17:37Z","timestamp":1458080257000},"page":"132-141","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":110,"special_numbering":"C","title":["Opposing roles of the triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells-like transcript 2 in microglia activation"],"prefix":"10.1016","volume":"42","author":[{"given":"Honghua","family":"Zheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Chen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Atagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Fen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longyu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wencan","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xilin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia S.","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terrone L.","family":"Rosenberry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Fryer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Wu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaxi","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guojun","family":"Bu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib1","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1126\/science.1227901","article-title":"Microglia: scapegoat, saboteur, or something else?","volume":"339","author":"Aguzzi","year":"2013","journal-title":"Science"},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib2","first-page":"1567","article-title":"TREM2 and neurodegenerative disease","volume":"369","author":"Benitez","year":"2013","journal-title":"N.\u00a0Engl. J. Med."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib3","doi-asserted-by":"crossref","first-page":"1510.e19","DOI":"10.1016\/j.neurobiolaging.2013.12.010","article-title":"Missense variant in TREML2 protects against Alzheimer's disease","volume":"35","author":"Benitez","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib4","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nrn2038","article-title":"Microglia-mediated neurotoxicity: uncovering the molecular mechanisms","volume":"8","author":"Block","year":"2007","journal-title":"Nat. Rev. Neurosci."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib5","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1038\/nri1106","article-title":"TREMs in the immune system and beyond","volume":"3","author":"Colonna","year":"2003","journal-title":"Nat. Rev. Immunol."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib6","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.coi.2009.01.009","article-title":"TREM and TREM-like receptors in inflammation and disease","volume":"21","author":"Ford","year":"2009","journal-title":"Curr. Opin. Immunol."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib7","first-page":"307","article-title":"Microglial response to amyloid plaques in APPsw transgenic mice","volume":"152","author":"Frautschy","year":"1998","journal-title":"Am. J. Pathol."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib8","doi-asserted-by":"crossref","first-page":"921","DOI":"10.3892\/mmr.2013.1268","article-title":"Silencing of triggering receptor expressed on myeloid cells-2 enhances the inflammatory responses of alveolar macrophages to lipopolysaccharide","volume":"7","author":"Gao","year":"2013","journal-title":"Mol. Med. Rep."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib9","first-page":"1569","article-title":"TREM2 and neurodegenerative disease","volume":"369","author":"Guerreiro","year":"2013","journal-title":"N.\u00a0Engl. J. Med."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib10","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1056\/NEJMoa1211851","article-title":"TREM2 variants in Alzheimer's disease","volume":"368","author":"Guerreiro","year":"2013","journal-title":"N.\u00a0Engl. J. Med."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib11","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.4049\/jimmunol.177.4.2051","article-title":"Cutting edge: inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12","volume":"177","author":"Hamerman","year":"2006","journal-title":"J.\u00a0Immunol."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib12","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/S1474-4422(15)70016-5","article-title":"Neuroinflammation in Alzheimer's disease","volume":"14","author":"Heneka","year":"2015","journal-title":"Lancet Neurol."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib13","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1111\/j.1471-4159.2009.06042.x","article-title":"A\u00a0role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia","volume":"109","author":"Hsieh","year":"2009","journal-title":"J.\u00a0Neurochem."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib14","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.1016\/j.jmb.2015.04.004","article-title":"Antiparallel beta-sheet structure within the C-Terminal region of 42-Residue Alzheimer's amyloid-beta peptides when they form 150-kDa oligomers","volume":"427","author":"Huang","year":"2015","journal-title":"J.\u00a0Mol. Biol."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib15","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1002\/eji.201141679","article-title":"TREM-2, triggering receptor expressed on myeloid cell-2, negatively regulates TLR responses in dendritic cells","volume":"42","author":"Ito","year":"2012","journal-title":"Eur. J. Immunol."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib16","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1084\/jem.20142322","article-title":"TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models","volume":"212","author":"Jay","year":"2015","journal-title":"J.\u00a0Exp. Med."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib17","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1007\/s12035-013-8424-8","article-title":"TREM2 in Alzheimer's disease","volume":"48","author":"Jiang","year":"2013","journal-title":"Mol. Neurobiol."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib18","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1016\/j.neurobiolaging.2013.11.026","article-title":"Triggering receptor expressed on myeloid cells 2 knockdown exacerbates aging-related neuroinflammation and cognitive deficiency in senescence-accelerated mouse prone 8 mice","volume":"35","author":"Jiang","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib19","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1056\/NEJMoa1211103","article-title":"Variant of TREM2 associated with the risk of Alzheimer's disease","volume":"368","author":"Jonsson","year":"2013","journal-title":"N.\u00a0Engl. J. Med."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib20","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1152\/physrev.00011.2010","article-title":"Physiology of microglia","volume":"91","author":"Kettenmann","year":"2011","journal-title":"Physiol. Rev."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib21","doi-asserted-by":"crossref","first-page":"6012","DOI":"10.4049\/jimmunol.176.10.6012","article-title":"Trem-like transcript 2 is expressed on cells of the myeloid\/granuloid and B lymphoid lineage and is up-regulated in response to inflammation","volume":"176","author":"King","year":"2006","journal-title":"J.\u00a0Immunol."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib22","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1038\/ni1411","article-title":"The TREM receptor family and signal integration","volume":"7","author":"Klesney-Tait","year":"2006","journal-title":"Nat. Immunol."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib23","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1750-1326-9-33","article-title":"Temporal gene profiling of the 5XFAD transgenic mouse model highlights the importance of microglial activation in Alzheimer's disease","volume":"9","author":"Landel","year":"2014","journal-title":"Mol. Neurodegener."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib24","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/0306-4522(90)90229-W","article-title":"Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain","volume":"39","author":"Lawson","year":"1990","journal-title":"Neuroscience"},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib25","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1007\/s00702-010-0433-4","article-title":"The role of microglia in amyloid clearance from the AD brain","volume":"117","author":"Lee","year":"2010","journal-title":"J.\u00a0Neural. Transm."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib26","first-page":"48","article-title":"Macrophage colony-stimulating factor mediates astrocyte-induced microglial ramification in human fetal central nervous system culture","volume":"145","author":"Liu","year":"1994","journal-title":"Am. J. Pathol."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib27","doi-asserted-by":"crossref","first-page":"29889","DOI":"10.1074\/jbc.M200868200","article-title":"Accelerated phagocytosis of amyloid-beta by mouse and human microglia overexpressing the macrophage colony-stimulating factor receptor","volume":"277","author":"Mitrasinovic","year":"2002","journal-title":"J.\u00a0Biol. Chem."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib28","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1016\/j.biocel.2010.06.021","article-title":"Microglia: proliferation and activation driven by the P2X7 receptor","volume":"42","author":"Monif","year":"2010","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib29","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1016\/j.bcp.2014.01.008","article-title":"Microglial dysfunction in brain aging and Alzheimer's disease","volume":"88","author":"Mosher","year":"2014","journal-title":"Biochem. Pharmacol."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib30","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1083\/jcb.200808080","article-title":"TREM-2 (triggering receptor expressed on myeloid cells 2) is a phagocytic receptor for bacteria","volume":"184","author":"N'Diaye","year":"2009","journal-title":"J.\u00a0Cell Biol."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib31","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.jneuroim.2006.11.032","article-title":"Essential role of the microglial triggering receptor expressed on myeloid cells-2 (TREM2) for central nervous tissue immune homeostasis","volume":"184","author":"Neumann","year":"2007","journal-title":"J.\u00a0Neuroimmunol."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1515\/REVNEURO.2009.20.1.1","article-title":"Is Alzheimer's disease a result of presynaptic failure? Synaptic dysfunctions induced by oligomeric beta-amyloid","volume":"20","author":"Nimmrich","year":"2009","journal-title":"Rev. Neurosci."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib33","doi-asserted-by":"crossref","first-page":"2612","DOI":"10.4049\/jimmunol.1102836","article-title":"TREM2 and beta-catenin regulate bone homeostasis by controlling the rate of osteoclastogenesis","volume":"188","author":"Otero","year":"2012","journal-title":"J.\u00a0Immunol."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib34","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s13024-015-0040-9","article-title":"TREM2 in CNS homeostasis and neurodegenerative disease","volume":"10","author":"Painter","year":"2015","journal-title":"Mol. Neurodegener."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib35","doi-asserted-by":"crossref","first-page":"ra38","DOI":"10.1126\/scisignal.2000500","article-title":"TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1","volume":"3","author":"Peng","year":"2010","journal-title":"Sci. Signal."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib36","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/0304-3940(90)90748-X","article-title":"Morphologic association between microglia and senile plaque amyloid in Alzheimer's disease","volume":"119","author":"Perlmutter","year":"1990","journal-title":"Neurosci. Lett."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib37","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.pneurobio.2010.06.009","article-title":"Microglia and neuroprotection: from in\u00a0vitro studies to therapeutic applications","volume":"92","author":"Polazzi","year":"2010","journal-title":"Prog. Neurobiol."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib38","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1146\/annurev.immunol.021908.132528","article-title":"Microglial physiology: unique stimuli, specialized responses","volume":"27","author":"Ransohoff","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib39","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/1750-1326-9-56","article-title":"Interleukin-1beta causes excitotoxic neurodegeneration and multiple sclerosis disease progression by activating the apoptotic protein p53","volume":"9","author":"Rossi","year":"2014","journal-title":"Mol. Neurodegener."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib40","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1111\/j.1471-4159.2009.06130.x","article-title":"The surface-exposed chaperone, Hsp60, is an agonist of the microglial TREM2 receptor","volume":"110","author":"Stefano","year":"2009","journal-title":"J.\u00a0Neurochem."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/jnr.20093","article-title":"Microglia and Alzheimer's disease pathogenesis","volume":"77","author":"Streit","year":"2004","journal-title":"J.\u00a0Neurosci. Res."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib42","doi-asserted-by":"crossref","first-page":"3451","DOI":"10.1167\/iovs.12-10938","article-title":"TREM-2 promotes host resistance against Pseudomonas aeruginosa infection by suppressing corneal inflammation via a PI3K\/Akt signaling pathway","volume":"54","author":"Sun","year":"2013","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib43","doi-asserted-by":"crossref","first-page":"e124","DOI":"10.1371\/journal.pmed.0040124","article-title":"TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis","volume":"4","author":"Takahashi","year":"2007","journal-title":"PLoS Med."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib44","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1084\/jem.20041611","article-title":"Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2","volume":"201","author":"Takahashi","year":"2005","journal-title":"J.\u00a0Exp. Med."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib45","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/1750-1326-9-48","article-title":"Oligomeric abeta-induced synaptic dysfunction in Alzheimer's disease","volume":"9","author":"Tu","year":"2014","journal-title":"Mol. Neurodegener."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib46","doi-asserted-by":"crossref","first-page":"3520","DOI":"10.4049\/jimmunol.177.6.3520","article-title":"Cutting edge: TREM-2 attenuates macrophage activation","volume":"177","author":"Turnbull","year":"2006","journal-title":"J.\u00a0Immunol."},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib47","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/j.cell.2015.01.049","article-title":"TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model","volume":"160","author":"Wang","year":"2015","journal-title":"Cell"},{"key":"10.1016\/j.neurobiolaging.2016.03.004_bib48","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1111\/j.1471-4159.2010.06763.x","article-title":"Excitotoxicity of TNFalpha derived from KA activated microglia on hippocampal neurons in\u00a0vitro and in\u00a0vivo","volume":"114","author":"Zhu","year":"2010","journal-title":"J.\u00a0Neurochem."}],"container-title":["Neurobiology of Aging"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0197458016002025?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0197458016002025?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2019,11,2]],"date-time":"2019-11-02T05:04:27Z","timestamp":1572671067000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0197458016002025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,6]]},"references-count":48,"alternative-id":["S0197458016002025"],"URL":"https:\/\/doi.org\/10.1016\/j.neurobiolaging.2016.03.004","relation":{},"ISSN":["0197-4580"],"issn-type":[{"value":"0197-4580","type":"print"}],"subject":[],"published":{"date-parts":[[2016,6]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Opposing roles of the triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells-like transcript 2 in microglia activation","name":"articletitle","label":"Article Title"},{"value":"Neurobiology of Aging","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.neurobiolaging.2016.03.004","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2016 Elsevier Inc. All rights reserved.","name":"copyright","label":"Copyright"}]}}