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OL maintain neuronal health through myelin axon interactions and by supplying neurotrophic and metabolic support. To gain insight on how OL and myelin may improve neuronal deficits associated with AD, we have generated a novel mouse model (AD\/cKO) by crossing the App\n                  <jats:sup>NL-G-F<\/jats:sup>\n                  mouse which carries three human AD mutations in the mouse\n                  <jats:italic>App<\/jats:italic>\n                  gene with the\n                  <jats:italic>\n                    Fus\n                    <jats:sup>OL<\/jats:sup>\n                  <\/jats:italic>\n                  cKO, which has thicker myelin associated with greater cholesterol biosynthesis. The spatial working memory deficits manifested by the aged AD mouse were fully rescued by the\n                  <jats:italic>\n                    Fus\n                    <jats:sup>OL<\/jats:sup>\n                  <\/jats:italic>\n                  cKO. This outcome was associated with reduced neuronal oxidative damage, preserved presynaptic structures at the plaque niches and a shift in microglia state at the niches in both hippocampus and cortex. In contrast, plaque burden and microglia density were decreased in the hippocampus but not in cortex, uncoupling the neuronal and microglia effects from the amyloid burden. Single cell transcriptomics of AD\/cKO hippocampal OL revealed upregulation of energy metabolism and antioxidant genes, suggesting a role of OL enhanced energy metabolism in protecting neurons and affecting microglia state in AD pathology.\n                <\/jats:p>","DOI":"10.1101\/2025.11.24.689041","type":"posted-content","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T19:40:18Z","timestamp":1764186018000},"source":"Crossref","is-referenced-by-count":1,"title":["<i>Fus<\/i>\n                  depleted oligodendrocytes reduce neuronal damage and attenuate AD progression in the App\n                  <sup>NL-G-F<\/sup>\n                  mouse"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0712-4861","authenticated-orcid":false,"given":"Te-Hsuan","family":"Tung","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6012-8936","authenticated-orcid":false,"given":"Sudhagar","family":"Babu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6891-4049","authenticated-orcid":false,"given":"Xiangting","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2187-0371","authenticated-orcid":false,"given":"Alec","family":"Sciutto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micah","family":"Romer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prathima","family":"Racha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2113-8442","authenticated-orcid":false,"given":"Victoria","family":"Fisler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrita","family":"Saha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9659-9251","authenticated-orcid":false,"given":"Takashi","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1970-6903","authenticated-orcid":false,"given":"Takaomi C.","family":"Saido","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0940-5314","authenticated-orcid":false,"given":"Judith B.","family":"Grinspan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0186-2115","authenticated-orcid":false,"given":"Hansruedi","family":"Mathys","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2507-3295","authenticated-orcid":false,"given":"Takashi D. 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