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Nesfatin-1 (NF-1), a neuropeptide involved in regulating appetite and energy homeostasis, has not been extensively studied for its pathophysiological role in AD. In this study, we found that NF-1 treatment improved cellular senescence in brain vascular endothelial bEnd.3 cells by restoring the expression of hTERT and TERF2 against oligomerized A\u03b2<jats:sub>1-42<\/jats:sub>. Additionally, NF-1 reduced p53 and p21 protein levels in bEnd.3 cells exposed to oligomerized A\u03b2<jats:sub>1-42<\/jats:sub>. Notably, NF-1 reduced oligomerized A\u03b2<jats:sub>1-42<\/jats:sub>-induced endothelial monolayer permeability by maintaining transendothelial electric resistance (TEER) and the levels of tight junction proteins claudin 5 and ZO-1. Furthermore, NF-1 suppressed the expression of VEGF-R1 but not VEGF-R2 in bEnd.3 cells exposed to oligomerized A\u03b2<jats:sub>1-42<\/jats:sub>. Overexpression of VEGF-R1 negated the protective effects of NF-1 against oligomerized A\u03b2<jats:sub>1-42<\/jats:sub>-induced cellular senescence and increased endothelial monolayer permeability, indicating the involvement of VEGF-R1 in this process. Using a transgenic (Tg APPswe\/PSEN1dE9) AD mouse model, we demonstrated that NF-1 administration lowered VEGF-R1 expression in the brain cortex of AD mice. Moreover, NF-1 mitigated BBB dysfunction and enhanced the expression of claudin 5 and ZO-1 in the brains of AD mice. Our results suggest that NF-1 may be a potential therapeutic strategy for treating AD.<\/jats:p>","DOI":"10.1038\/s41398-025-03528-8","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T06:16:50Z","timestamp":1756880210000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Nesfatin-1 ameliorates blood-brain barrier dysfunction in Alzheimer\u2019s disease by targeting VEGF-R1 and reducing cellular senescence in brain vascular endothelial cells"],"prefix":"10.1038","volume":"15","author":[{"given":"Biyue","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shumei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeming","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunzhan","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Futian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1222-3168","authenticated-orcid":false,"given":"Huasong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,3]]},"reference":[{"key":"3528_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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