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Genetic loss of or decreased TREM2 function impairs the microglial response to amyloid-\u03b2 (A\u03b2) plaques, resulting in more diffuse A\u03b2 plaques and increased peri-plaque neuritic dystrophy and AD-tau seeding. Thus, microglia and TREM2 are at a critical intersection of A\u03b2 and tau pathologies in AD. Since genetically decreasing TREM2 function increases A\u03b2-induced tau seeding, we hypothesized that chronically increasing TREM2 signaling would decrease amyloid-induced tau-seeding and spreading. Using a mouse model of amyloidosis in which AD-tau is injected into the brain to induce A\u03b2-dependent tau seeding\/spreading, we found that chronic administration of an activating TREM2 antibody increases peri-plaque microglial activation but surprisingly increases peri-plaque NP-tau pathology and neuritic dystrophy, without altering A\u03b2 plaque burden. Our data suggest that sustained microglial activation through TREM2 that does not result in strong amyloid removal may exacerbate A\u03b2-induced tau pathology, which may have important clinical implications.<\/jats:p>","DOI":"10.1084\/jem.20220654","type":"journal-article","created":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T02:21:41Z","timestamp":1662690101000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":154,"title":["Chronic TREM2 activation exacerbates A\u03b2-associated tau seeding and spreading"],"prefix":"10.1084","volume":"220","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5360-5466","authenticated-orcid":true,"given":"Nimansha","family":"Jain","sequence":"first","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, MO 1"},{"name":"Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 2"},{"name":"Knight Alzheimer\u2019s Disease Research Center, Washington University School of Medicine, St. Louis, MO 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0256-0947","authenticated-orcid":true,"given":"Caroline A.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, MO 1"},{"name":"Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 2"},{"name":"Knight Alzheimer\u2019s Disease Research Center, Washington University School of Medicine, St. Louis, MO 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4743-926X","authenticated-orcid":true,"given":"Jason D.","family":"Ulrich","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, MO 1"},{"name":"Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 2"},{"name":"Knight Alzheimer\u2019s Disease Research Center, Washington University School of Medicine, St. Louis, MO 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3400-0856","authenticated-orcid":true,"given":"David M.","family":"Holtzman","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, MO 1"},{"name":"Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 2"},{"name":"Knight Alzheimer\u2019s Disease Research Center, Washington University School of Medicine, St. Louis, MO 3"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2022,10,11]]},"reference":[{"key":"2022101321104913500_bib1","doi-asserted-by":"publisher","first-page":"26043","DOI":"10.1074\/jbc.M115.679043","article-title":"Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2)","volume":"290","author":"Atagi","year":"2015","journal-title":"J. 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