{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T23:20:26Z","timestamp":1788477626603,"version":"build-2803163510"},"reference-count":35,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T00:00:00Z","timestamp":1773446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea (NRF) grant funded by the Korea government","doi-asserted-by":"publisher","award":["RS-2025-24873145"],"award-info":[{"award-number":["RS-2025-24873145"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is the most prevalent neurodegenerative disorder in the aging population. Drug repurposing provides a cost-effective strategy to identify novel therapeutics that may mitigate age-associated pathologies. Here, we report the therapeutic potential of fluoxetine, a selective serotonin reuptake inhibitor commonly used as an antidepressant, in alleviating cognitive impairment and AD-like pathology in 5xFAD mice, a transgenic model of familial AD. Chronic fluoxetine administration significantly ameliorated anxiety-like behavior and cognitive deficits in 5xFAD mice, as assessed by open field, Y-maze, and novel object recognition tests. Fluoxetine treatment was associated with reduced amyloid plaque deposition in the hippocampus and cortex, attenuation of microglial activation, and decreased expression of inflammatory cytokines. At the molecular level, fluoxetine increased phosphorylation of GSK3\u03b2 at Ser9, which was associated with enhanced CREB phosphorylation and upregulation of the \u03b1-secretase ADAM10. These effects were further examined in SH-SY5Y neuronal cells, where CREB phosphorylation and ADAM10 expression were significantly modulated by GSK3\u03b2 inhibition, whereas CaMKII inhibition had no detectable effect under our experimental conditions. Our findings suggest that fluoxetine modulates amyloid-associated signaling pathways in the 5xFAD model, in part through regulation of the GSK3\u03b2-CREB signaling framework. These results provide mechanistic insight into how fluoxetine may influence APP processing in an amyloid-driven pathological context, although further studies are required to clarify its translational implications in human AD.<\/jats:p>","DOI":"10.3390\/ijms27062676","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T10:10:43Z","timestamp":1773655843000},"page":"2676","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Fluoxetine Repurposing Mitigates Alzheimer\u2019s Disease Pathology via the GSK3\u03b2\u2013CREB\u2013ADAM10 Axis"],"prefix":"10.3390","volume":"27","author":[{"given":"Soo-Ho","family":"Lee","sequence":"first","affiliation":[{"name":"Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea"},{"name":"KNU G-LAMP Project Group, KNU Institute of Basic Sciences, School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu 41566, Republic of Korea"},{"name":"BK21 FOUR KNU Creative BioResearch Group, School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeonghoon","family":"Son","sequence":"additional","affiliation":[{"name":"Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyosun","family":"Jang","sequence":"additional","affiliation":[{"name":"Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun-Yong","family":"Kim","sequence":"additional","affiliation":[{"name":"New Drug Development Center, Osong Medical Innovation Foundation, Cheongju 28160, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0307-3390","authenticated-orcid":false,"given":"Kwang Seok","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3837-9867","authenticated-orcid":false,"given":"Hyun-Shik","family":"Lee","sequence":"additional","affiliation":[{"name":"KNU G-LAMP Project Group, KNU Institute of Basic Sciences, School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu 41566, Republic of Korea"},{"name":"BK21 FOUR KNU Creative BioResearch Group, School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hae-June","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea"},{"name":"Veterinary Medical Research Institute, College of Veterinary Medicine, Jeju National University, Jeju 63243, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e105","DOI":"10.1016\/S2468-2667(21)00249-8","article-title":"Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: An analysis for the Global Burden of Disease Study 2019","volume":"7","author":"Nichols","year":"2022","journal-title":"Lancet Public Health"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s13024-022-00574-4","article-title":"ApoE in Alzheimer\u2019s disease: Pathophysiology and therapeutic strategies","volume":"17","author":"Raulin","year":"2022","journal-title":"Mol. 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