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Current therapies primarily target inflammation, with limited strategies to promote remyelination or neural repair. This study explores the therapeutic potential of Brain\u2010Derived Neurotrophic Factor (BDNF) delivered via an adeno\u2010associated virus (AAV) vector to enhance remyelination and improve cognitive function in a subchronic cuprizone (CPZ)\u2010induced demyelination mouse model. Sixty female C57BL\/6 mice were used, with half receiving a 7\u2010week CPZ diet to induce oligodendrocyte loss. After demyelination, mice were treated with AAV\u2010BDNF, AAV\u2010eGFP, or saline injections into the corpus callosum (CC), followed by a 5\u2010week recovery phase. Behavioral assessments revealed improved cognitive performance with BDNF treatment, demonstrated by increased latency in passive avoidance tests. Immunofluorescence analysis showed increased proliferation and maturation of oligodendrocyte progenitor cells, with higher PDGFR\u03b1 and CC1 markers, alongside elevated MBP. Transmission electron microscopy (TEM) indicated thicker myelin sheaths and a higher percentage of myelinated axons in AAV\u2010BDNF\u2010treated mice. Mitochondrial analyses revealed that BDNF treatment preserved mitochondrial integrity, with reduced swelling and improved structural regularity. Inflammatory markers showed no differences in Iba1 but indicated a trend of reduced astrocytic activation with BDNF. These results demonstrate that AAV\u2010BDNF therapy enhances remyelination, myelin integrity, mitochondrial structure, and cognitive function in a CPZ model, underscoring its potential for treating MS. BDNF\u2010based strategies may offer innovative avenues to improve neurological recovery and address unmet needs in MS management.<\/jats:p>","DOI":"10.1002\/glia.70058","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T09:51:09Z","timestamp":1754473869000},"page":"2189-2205","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["<scp>AAV<\/scp>\u2010Based Intracerebral Administration of <scp>BDNF<\/scp> Promotes Myelin Repair and Cognitive Improvement After\u00a0Cuprizone\u2010Induced Demyelination"],"prefix":"10.1002","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4075-2445","authenticated-orcid":false,"given":"Yousra","family":"El Ouaamari","sequence":"first","affiliation":[{"name":"Laboratory of Experimental Haematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences University of Antwerp  Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Ricciardi","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Haematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences University of Antwerp  Antwerp Belgium"},{"name":"\u03bcNEURO Research Centre of Excellence University of Antwerp  Antwerp Belgium"},{"name":"Bio\u2010Imaging Lab (BIL) University of Antwerp  Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanne","family":"van der Heijden","sequence":"additional","affiliation":[{"name":"Center for Oncology Research (CORE), Integrated Personalized &amp; 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Behaviour Group, Experimental Neurobiology Unit (ENU), Department of Biomedical Sciences University of Antwerp  Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elke","family":"Calus","sequence":"additional","affiliation":[{"name":"Neurochemistry &amp; Behaviour Group, Experimental Neurobiology Unit (ENU), Department of Biomedical Sciences University of Antwerp  Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Kuhn","sequence":"additional","affiliation":[{"name":"Wellcome Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science Queen's University Belfast  Northern Ireland UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waleed","family":"Marei","sequence":"additional","affiliation":[{"name":"Gamete Research Centre, Department of Veterinary Sciences University of Antwerp  Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne","family":"Dombrowski","sequence":"additional","affiliation":[{"name":"Wellcome Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science Queen's University Belfast  Northern Ireland UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marleen","family":"Verhoye","sequence":"additional","affiliation":[{"name":"\u03bcNEURO Research Centre of Excellence University of Antwerp  Antwerp Belgium"},{"name":"Bio\u2010Imaging Lab (BIL) University of Antwerp  Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1892-6499","authenticated-orcid":false,"given":"Peter","family":"Ponsaerts","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Haematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences University of Antwerp  Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inez","family":"Wens","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Haematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences University of Antwerp  Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Cools","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Haematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences University of Antwerp  Antwerp Belgium"},{"name":"Center for Cell Therapy and Regenerative Medicine, Laboratory of Experimental Haematology Antwerp University Hospital  Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,6]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2013.06.012"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(20)30277-5"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13745"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-09-03221.2000"},{"key":"e_1_2_13_6_1","first-page":"407","article-title":"Current Stem Cell Autologous Mesenchymal Stem Cell Therapy in Progressive Multiple Sclerosis: An Open Label Study","volume":"7","author":"Bonab M. 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