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We observed that hippocampal tissue from AD patients exhibits a marked reduction in\n                    <jats:italic>O<\/jats:italic>\n                    -GlcNAcylation, accompanied by enhanced pro-inflammatory M1 microglial polarization, elevated NF-\u03baB signaling, and NLRP3 inflammasome activation. In an LPS-induced neuroinflammation model exhibiting AD-relevant inflammatory and cognitive features, as well as in in vitro microglial cultures, LPS exposure led to a pronounced decrease in\n                    <jats:italic>O<\/jats:italic>\n                    -GlcNAcylation, particularly within Iba1-positive microglia. Systemic or in vitro treatment with glucosamine (GlcN) effectively restored\n                    <jats:italic>O<\/jats:italic>\n                    -GlcNAc levels, suppressed M1-associated inflammatory pathways, and promoted an anti-inflammatory M2 phenotype. Mechanistically, GlcN enhanced\n                    <jats:italic>O<\/jats:italic>\n                    -GlcNAcylation of NF-\u03baB subunits p65 and c-Rel, limiting their nuclear translocation and downstream pro-inflammatory gene expression. Notably, GlcN treatment ameliorated LPS-induced memory deficits and neuronal loss in mice. Collectively, these findings suggest that\n                    <jats:italic>O<\/jats:italic>\n                    -GlcNAcylation acts as a modulatory regulator of microglial activation and neuroinflammation in AD, and that enhancing\n                    <jats:italic>O<\/jats:italic>\n                    -GlcNAcylation may represent a potential therapeutic strategy to preserve immune homeostasis and neuronal integrity.\n                  <\/jats:p>","DOI":"10.1038\/s41419-026-08862-3","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T01:42:40Z","timestamp":1779327760000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["O-GlcNAcylation reprograms microglial inflammatory states and attenuates Alzheimer\u2019s disease pathology"],"prefix":"10.1038","volume":"17","author":[{"given":"Dong Yeol","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Min","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanhaeng","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3000-8428","authenticated-orcid":false,"given":"Inn-Oc","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"key":"8862_CR1","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","volume":"397","author":"P Scheltens","year":"2021","unstructured":"Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chetelat G, Teunissen CE, et al. 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