{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T01:58:15Z","timestamp":1788400695448,"version":"build-2803163510"},"reference-count":139,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T00:00:00Z","timestamp":1757116800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondo de Investigaciones Sanitarias (FIS)","award":["PI15\/00601"],"award-info":[{"award-number":["PI15\/00601"]}]},{"name":"European Regional Development Fund and European Social Fund \u201cInvesting in your future\u201d","award":["PI15\/00601"],"award-info":[{"award-number":["PI15\/00601"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system (CNS) characterized by oligodendrocyte (OLG) degeneration, myelin loss, and impaired remyelination. Apolipoprotein D (Apo D), a glia-derived lipocalin, has emerged in recent decades as a neuroprotective molecule involved in lipid transport, oxidative stress regulation, and inflammation control during aging and neurodegenerative diseases like MS. However, its role in demyelination\/remyelination dynamics remains poorly defined. In this study, we used the cuprizone (CPZ)-induced demyelination model in C57BL\/6 mice to analyze Apo D expression patterns in the corpus callosum during de- and remyelination. We also assessed whether the atypical antipsychotic clozapine (CLO), previously shown to upregulate Apo D in vivo, could modulate its expression and influence myelin recovery in this pathological context. Using a combination of magnetic resonance imaging, Luxol fast blue staining, and double immunohistochemistry, we demonstrated that CPZ treatment for 3 or 6 weeks led to significant demyelination, hydrocephalus, and reduced motor cortex thickness, which were partially reversed after treatment cessation. Apo D expression in OLGs was significantly reduced by CPZ exposure, both at the protein level and in terms of immunoreactive cell counts, but was restored following treatment withdrawal. Notably, co-administration of CLO prevented the CPZ-induced reduction in Apo D expression in OLGs, although it did not attenuate myelin loss. In this way, our results reveal a strong correlation between Apo D expression and OLG\/myelin integrity in vivo. While CLO did not exert remyelinating effects, it preserved Apo D levels under demyelinating conditions, suggesting a potential indirect neuroprotective mechanism. These findings support the relevance of Apo D in CNS myelin homeostasis and highlight its potential as a molecular target for therapeutic intervention in demyelinating diseases such as MS.<\/jats:p>","DOI":"10.3390\/ijms26178692","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T10:27:12Z","timestamp":1757500032000},"page":"8692","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Apolipoprotein D Expression Dynamics During Cuprizone-Induced Demyelination and Remyelination in a Mouse Model of Multiple Sclerosis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0572-0926","authenticated-orcid":false,"given":"Eva","family":"Mart\u00ednez-Pinilla","sequence":"first","affiliation":[{"name":"Department of Morphology and Cell Biology, University of Oviedo, 33006 Oviedo, Spain"},{"name":"Instituto de Neurociencias del Principado de Asturias (INEUROPA), 33006 Oviedo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias (ISPA), 33006 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2699-6331","authenticated-orcid":false,"given":"Nuria","family":"Rubio-Sard\u00f3n","sequence":"additional","affiliation":[{"name":"Department of Morphology and Cell Biology, University of Oviedo, 33006 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3472-2840","authenticated-orcid":false,"given":"Gemma","family":"Fern\u00e1ndez-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias (ISPA), 33006 Oviedo, Spain"},{"name":"Department of Functional Biology, University of Oviedo, 33006 Oviedo, Spain"},{"name":"Instituto Universitario de Oncolog\u00eda del Principado de Asturias (IUOPA), 33006 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Villar-Conde","sequence":"additional","affiliation":[{"name":"Department of Morphology and Cell Biology, University of Oviedo, 33006 Oviedo, Spain"},{"name":"Instituto de Neurociencias del Principado de Asturias (INEUROPA), 33006 Oviedo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias (ISPA), 33006 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0154-9826","authenticated-orcid":false,"given":"Carlota","family":"Men\u00e9ndez-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Department of Morphology and Cell Biology, University of Oviedo, 33006 Oviedo, Spain"},{"name":"Instituto de Neurociencias del Principado de Asturias (INEUROPA), 33006 Oviedo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias (ISPA), 33006 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8984-8849","authenticated-orcid":false,"given":"Jorge","family":"Tolivia","sequence":"additional","affiliation":[{"name":"Department of Morphology and Cell Biology, University of Oviedo, 33006 Oviedo, Spain"},{"name":"Instituto de Neurociencias del Principado de Asturias (INEUROPA), 33006 Oviedo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias (ISPA), 33006 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7959-4790","authenticated-orcid":false,"given":"Eva","family":"del Valle","sequence":"additional","affiliation":[{"name":"Department of Morphology and Cell Biology, University of Oviedo, 33006 Oviedo, Spain"},{"name":"Instituto de Neurociencias del Principado de Asturias (INEUROPA), 33006 Oviedo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias (ISPA), 33006 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6206-6505","authenticated-orcid":false,"given":"Ana","family":"Navarro","sequence":"additional","affiliation":[{"name":"Department of Morphology and Cell Biology, University of Oviedo, 33006 Oviedo, Spain"},{"name":"Instituto de Neurociencias del Principado de Asturias (INEUROPA), 33006 Oviedo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias (ISPA), 33006 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1056\/NEJMra1401483","article-title":"Multiple sclerosis","volume":"378","author":"Reich","year":"2018","journal-title":"N. 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