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However, the exact cellular and chemical mediators of neuroinflammation in AD remain poorly understood. The oxysterol 25-hydroxycholesterol (25-HC) is an important immunomodulator produced by peripheral macrophages with wide-ranging effects on cell signaling and innate immunity. Cholesterol 25-hydroxylase (CH25H), the enzyme responsible for 25-HC production, has also been found to be one of the disease-associated microglial (DAM) genes that are upregulated in the brain of AD and AD transgenic mouse models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used real-time PCR and immunoblotting to examine CH25H expression in human AD brain tissue and in transgenic mouse brain tissue-bearing amyloid-\u03b2 plaques or tau pathology. The innate immune response of primary mouse microglia under different treatment conditions or bearing different genetic backgrounds was analyzed using ELISA, western blotting, or immunocytochemistry.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We found that CH25H expression is upregulated in human AD brain tissue and in transgenic mouse brain tissue-bearing amyloid-\u03b2 plaques or tau pathology. Treatment with the toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) markedly upregulates CH25H expression in the mouse brain and stimulates CH25H expression and 25-HC secretion in mouse primary microglia. We found that LPS-induced microglial production of the pro-inflammatory cytokine IL-1\u03b2 is markedly potentiated by 25-HC and attenuated by the deletion of CH25H. Microglia expressing apolipoprotein E4 (apoE4), a genetic risk factor for AD, produce greater amounts of 25-HC than apoE3-expressing microglia following treatment with LPS. Remarkably, 25-HC treatment results in a greater level of IL-1\u03b2 secretion in LPS-activated apoE4-expressing microglia than in apoE2- or apoE3-expressing microglia. Blocking potassium efflux or inhibiting caspase-1 prevents 25-HC-potentiated IL-1\u03b2 release in apoE4-expressing microglia, indicating the involvement of caspase-1 inflammasome activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>25-HC may function as a microglial-secreted inflammatory mediator in the brain, promoting IL-1\u03b2-mediated neuroinflammation in an apoE isoform-dependent manner (E4&gt;&gt;E2\/E3) and thus may be an important mediator of neuroinflammation in AD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12974-020-01869-3","type":"journal-article","created":{"date-parts":[[2020,6,17]],"date-time":"2020-06-17T03:02:48Z","timestamp":1592362968000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":118,"title":["25-Hydroxycholesterol amplifies microglial IL-1\u03b2 production in an apoE isoform-dependent manner"],"prefix":"10.1186","volume":"17","author":[{"given":"Man Ying","family":"Wong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James J.","family":"Doherty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anil G.","family":"Cashikar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Amelianchik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svitlana","family":"Tymchuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick M.","family":"Sullivan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxing","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas F.","family":"Covey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory A.","family":"Petsko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Holtzman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"Paul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3752-8266","authenticated-orcid":false,"given":"Wenjie","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,6,17]]},"reference":[{"issue":"4","key":"1869_CR1","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1016\/S1474-4422(15)70016-5","volume":"14","author":"MT Heneka","year":"2015","unstructured":"Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. 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Cell. 2017;171(5):1057\u201371 e11.","journal-title":"Cell."}],"container-title":["Journal of Neuroinflammation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12974-020-01869-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12974-020-01869-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12974-020-01869-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T19:07:21Z","timestamp":1623870441000},"score":1,"resource":{"primary":{"URL":"https:\/\/jneuroinflammation.biomedcentral.com\/articles\/10.1186\/s12974-020-01869-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,17]]},"references-count":100,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["1869"],"URL":"https:\/\/doi.org\/10.1186\/s12974-020-01869-3","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.01.14.906966","asserted-by":"object"},{"id-type":"doi","id":"10.21203\/rs.3.rs-15868\/v1","asserted-by":"object"}]},"ISSN":["1742-2094"],"issn-type":[{"value":"1742-2094","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,17]]},"assertion":[{"value":"26 February 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 June 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 June 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All experiments were conducted in accordance with relevant NIH guidelines and regulations related to the Care and Use of Laboratory Animals and human tissue. Animal procedures were performed according to protocols approved by the Research Animal Resource Center at Weill Cornell Medicine.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"S.M. Paul is a founder, board member, and shareholder of Sage Therapeutics and Voyager Therapeutics. He\u2019s also CEO, board member and shareholder of Karuna Therapeutics and a board member and shareholder of Alnylam Pharmaceuticals as well as a venture partner at Third Rock Ventures. D.F. Covey is a founder and shareholder in Sage Therapeutics. J Doherty and M Lewis are employees and shareholders of Sage Therapeutics. D.M. Holtzman is listed as an inventor on a patent licensed by Washington University to C2N Diagnostics on the therapeutic use of anti-tau antibodies. D.M. Holtzman co-founded and is on the scientific advisory board of C2N Diagnostics, LLC. C2N Diagnostics, LLC has licensed certain anti-tau antibodies to AbbVie for therapeutic development. D.M. Holtzman is on the scientific advisory board of Denali and consults for Genentech and Idorsia. G.A.P. is on the scientific advisory boards of MeiraGTx, which develops gene therapies for neurodegenerative disorders including AD, and of Amicus Therapeutics and ProClara Biosciences. All other authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"192"}}