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In all cell types, a soluble 17\u00a0kDa N\u2010terminal cleavage fragment was shed into the conditioned media in a constitutive process that is inhibited by G1254023X and metalloprotease inhibitors and siRNA targeting ADAM10. Inhibitors of serine proteases and matrix metalloproteinases 2\/9, and ADAM17 siRNA did not block TREM2 shedding. Peptidomimetic protease inhibitors highlighted a possible cleavage site, and mass spectrometry confirmed that shedding occurred predominantly at the H157\u2010S158 peptide bond for both wild\u2010type and H157Y human TREM2 and for the wild\u2010type murine orthologue. Crucially, we also show that the Alzheimer's disease\u2010associated H157Y TREM2 variant was shed more rapidly than wild type from HEK293 cells, possibly by a novel, batimastat\u2010 and ADAM10\u2010siRNA\u2010independent, sheddase activity. These insights offer new therapeutic targets for modulating the innate immune response in Alzheimer's and other neurological diseases.<\/jats:p>","DOI":"10.15252\/emmm.201707673","type":"journal-article","created":{"date-parts":[[2017,8,30]],"date-time":"2017-08-30T20:10:50Z","timestamp":1504123850000},"page":"1366-1378","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":203,"title":["TREM2 shedding by cleavage at the H157\u2010S158 bond is accelerated for the Alzheimer's disease\u2010associated H157Y variant"],"prefix":"10.1038","volume":"9","author":[{"given":"Peter","family":"Thornton","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Sevalle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J","family":"Deery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham","family":"Fraser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"St\u00e5hl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elske H","family":"Franssen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger B","family":"Dodd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seema","family":"Qamar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Gomez Perez\u2010Nievas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise SC","family":"Nicol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Eketj\u00e4ll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jefferson","family":"Revell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clare","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Billinton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter H","family":"St George\u2010Hyslop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iain","family":"Chessell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7791-1396","authenticated-orcid":false,"given":"Damian C","family":"Crowther","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,8,30]]},"reference":[{"key":"BFEMMM201707673_CR1","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1042\/BJ20090549","volume":"424","author":"CI Caescu","year":"2009","unstructured":"Caescu CI, Jeschke GR, Turk BE (2009) Active\u2010site determinants of substrate recognition by the metalloproteinases TACE and ADAM10. 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PT, GF, SS, EHF, RBD,\u00a0LSCN, SE, JR, AB, IC and DCC and are employees of AstraZeneca or its subsidiaries.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}