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The R47H variant of human TREM2 impairs ligand binding and increases Alzheimer\u2019s disease (AD) risk. In mouse models of amyloid \u03b2 (A\u03b2) accumulation, defective TREM2 function affects microglial response to A\u03b2 plaques, exacerbating tissue damage, whereas TREM2 overexpression attenuates pathology. Thus, AD may benefit from TREM2 activation. Here, we examined the impact of an anti-human TREM2 agonistic mAb, AL002c, in a mouse AD model expressing either the common variant (CV) or the R47H variant of TREM2. Single-cell RNA-seq of microglia after acute systemic administration of AL002c showed induction of proliferation in both CV- and R47H-transgenic mice. Prolonged administration of AL002c reduced filamentous plaques and neurite dystrophy, impacted behavior, and tempered microglial inflammatory response. We further showed that a variant of AL002c is safe and well tolerated in a first-in-human phase I clinical trial and engages TREM2 based on cerebrospinal fluid biomarkers. We conclude that AL002 is a promising candidate for AD therapy.<\/jats:p>","DOI":"10.1084\/jem.20200785","type":"journal-article","created":{"date-parts":[[2020,5,16]],"date-time":"2020-05-16T02:21:50Z","timestamp":1589595710000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":549,"title":["Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer\u2019s disease model"],"prefix":"10.1084","volume":"217","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1049-9127","authenticated-orcid":true,"given":"Shoutang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2638-9523","authenticated-orcid":true,"given":"Meer","family":"Mustafa","sequence":"additional","affiliation":[{"name":"Alector LLC, South San Francisco, CA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla M.","family":"Yuede","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurology, Washington University School of Medicine, St Louis, MO 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago Viveros","family":"Salazar","sequence":"additional","affiliation":[{"name":"Alector LLC, South San Francisco, CA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Kong","sequence":"additional","affiliation":[{"name":"Alector LLC, South San Francisco, CA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Long","sequence":"additional","affiliation":[{"name":"Alector LLC, South San Francisco, CA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Ward","sequence":"additional","affiliation":[{"name":"Alector LLC, South San Francisco, CA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omer","family":"Siddiqui","sequence":"additional","affiliation":[{"name":"Alector LLC, South San Francisco, CA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Paul","sequence":"additional","affiliation":[{"name":"Alector LLC, South San Francisco, CA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1672-0996","authenticated-orcid":true,"given":"Susan","family":"Gilfillan","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adiljan","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"Alector LLC, South San Francisco, CA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herv\u00e9","family":"Rhinn","sequence":"additional","affiliation":[{"name":"Alector LLC, South San Francisco, CA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Tassi","sequence":"additional","affiliation":[{"name":"Alector LLC, South San Francisco, CA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnon","family":"Rosenthal","sequence":"additional","affiliation":[{"name":"Alector LLC, South San Francisco, CA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Schwabe","sequence":"additional","affiliation":[{"name":"Alector LLC, South San Francisco, CA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5222-4987","authenticated-orcid":true,"given":"Marco","family":"Colonna","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2020,6,24]]},"reference":[{"key":"2023072812444460100_bib1","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.brainres.2017.12.028","article-title":"The locus coeruleus neuroprotective drug vindeburnol normalizes behavior in the 5xFAD transgenic mouse model of Alzheimer\u2019s disease","volume":"1702","author":"Braun","year":"2019","journal-title":"Brain Res"},{"key":"2023072812444460100_bib2","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1111\/imr.12350","article-title":"Mouse and human FcR effector functions","volume":"268","author":"Bruhns","year":"2015","journal-title":"Immunol. 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Spatial and temporal transcriptomics reveal microglia-astroglia crosstalk in the amyloid-\u03b2 plaque cell niche of Alzheimer\u2019s disease. bioRxiv. https:\/\/doi.org\/10.1101\/719930 (Preprint posted August 12, 2019).","DOI":"10.1101\/719930"},{"key":"2023072812444460100_bib5","doi-asserted-by":"publisher","first-page":"12620","DOI":"10.1074\/jbc.RA118.001848","article-title":"TREM2-activating antibodies abrogate the negative pleiotropic effects of the Alzheimer\u2019s disease variant Trem2R47H on murine myeloid cell function","volume":"293","author":"Cheng","year":"2018","journal-title":"J. Biol. Chem"},{"key":"2023072812444460100_bib6","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1038\/nn1472","article-title":"ATP mediates rapid microglial response to local brain injury in vivo","volume":"8","author":"Davalos","year":"2005","journal-title":"Nat. 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