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We demonstrated that 25HC impairs microglial surveillance, reduces phagocytic capacity, and increases the production of pro-inflammatory cytokines. <jats:italic>In vivo<\/jats:italic> two-photon microscopy revealed that 25HC administration diminishes microglial response to brain lesions, while flow cytometry confirmed reduced phagocytosis in both <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> models. Additionally, amyloid-beta (A\u03b2) was shown to upregulate <jats:italic>Ch25h<\/jats:italic> expression and elevate 25HC levels in microglia, exacerbating these functional impairments. Mechanistically, 25HC was found to enhance cholesterol esterification, disrupt cell membrane dynamics, and further reduce microglial mobility and phagocytosis. Treatment with Avasimibe, a cholesterol esterification inhibitor, restored membrane dynamics and microglial function, leading to attenuated AD pathology in a 5XFAD mouse model. These findings suggest that 25HC-induced changes in microglial function contribute to AD progression, and targeting cholesterol metabolism could offer therapeutic potential.<\/jats:p>","DOI":"10.1186\/s12974-025-03357-y","type":"journal-article","created":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T16:23:39Z","timestamp":1740500619000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["25-Hydroxycholesterol modulates microglial function and exacerbates Alzheimer\u2019s disease pathology: mechanistic insights and therapeutic potential of cholesterol esterification inhibition"],"prefix":"10.1186","volume":"22","author":[{"given":"Hayoung","family":"Choi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haeng Jun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Eun","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Ho","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihui","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"June-Hyun","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Do Yup","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunghoe","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inhee","family":"Mook-Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,25]]},"reference":[{"key":"3357_CR1","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1126\/science.1132813","volume":"314","author":"ED Roberson","year":"2006","unstructured":"Roberson ED, Mucke L. 100 years and counting: prospects for defeating Alzheimer\u2019s Disease. 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