{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:34:40Z","timestamp":1787027680011,"version":"build-2736575974"},"reference-count":66,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T00:00:00Z","timestamp":1755820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Henan Provincial Science and Technology Key Project","award":["242102310430"],"award-info":[{"award-number":["242102310430"]}]},{"name":"Henan Provincial Science and Technology Key Project","award":["202410478005"],"award-info":[{"award-number":["202410478005"]}]},{"name":"Henan Provincial Science and Technology Key Project","award":["26A180030"],"award-info":[{"award-number":["26A180030"]}]},{"name":"College Student Innovation and Entrepreneurship Training Program","award":["242102310430"],"award-info":[{"award-number":["242102310430"]}]},{"name":"College Student Innovation and Entrepreneurship Training Program","award":["202410478005"],"award-info":[{"award-number":["202410478005"]}]},{"name":"College Student Innovation and Entrepreneurship Training Program","award":["26A180030"],"award-info":[{"award-number":["26A180030"]}]},{"name":"key scientific research projects of higher education institutions in Henan Province","award":["242102310430"],"award-info":[{"award-number":["242102310430"]}]},{"name":"key scientific research projects of higher education institutions in Henan Province","award":["202410478005"],"award-info":[{"award-number":["202410478005"]}]},{"name":"key scientific research projects of higher education institutions in Henan Province","award":["26A180030"],"award-info":[{"award-number":["26A180030"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, with current therapies offering only limited symptomatic relief and lacking disease-modifying efficacy. Addressing this critical therapeutic gap, natural multi-target compounds like mulberroside A (MsA)\u2014a bioactive glycoside from Morus alba L.\u2014present promising alternatives. This study investigated MsA\u2019s neuroprotective potential using scopolamine-induced AD-like mice and N2a\/APP695swe cells. In vivo, MsA significantly ameliorated cognitive deficits and neuronal loss, concurrently enhancing cholinergic neurotransmission through increased acetylcholine levels and inhibited acetylcholinesterase (AChE)\/butyrylcholinesterase (BChE) activities. MsA also upregulated neurotrophic factors (BDNF, CREB) in critical brain regions. In vitro, MsA restored cholinergic function, mitigated oxidative stress, and crucially reduced amyloid-\u03b2 (A\u03b2) production by dual regulation of APP processing: promoting the non-amyloidogenic pathway via ADAM10 upregulation and inhibiting the amyloidogenic pathway via suppression of BACE1 and \u03b3-secretase components. Mechanistically, these multi-target benefits were mediated by MsA\u2019s activation of the PI3K\/AKT pathway, which triggered downstream inhibitory phosphorylation of GSK3\u03b2\u2014directly reduced tau hyperphosphorylation\u2014and activation of CREB\/BDNF signaling. Collectively, our findings demonstrate that MsA confers comprehensive neuroprotection against AD pathology by simultaneously targeting cholinergic dysfunction, oxidative stress, A\u03b2 accumulation, tau phosphorylation, and impaired neurotrophic signaling, highlighting its strong therapeutic candidacy.<\/jats:p>","DOI":"10.3390\/biology14091114","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T13:47:49Z","timestamp":1755870469000},"page":"1114","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mulberroside A: A Multi-Target Neuroprotective Agent in Alzheimer\u2019s Disease via Cholinergic Restoration and PI3K\/AKT Pathway Activation"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9878-7523","authenticated-orcid":false,"given":"Jin","family":"Li","sequence":"first","affiliation":[{"name":"Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China"},{"name":"Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou 466001, China"},{"name":"Fuxi Laboratory, Zhoukou Normal University, Zhoukou 466001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawen","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou 466001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaodong","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou 466001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Guo","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou 466001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziliang","family":"Jin","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou 466001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shourong","family":"Qiao","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou 466001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6680-5632","authenticated-orcid":false,"given":"Yunxia","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou 466001, China"},{"name":"Fuxi Laboratory, Zhoukou Normal University, Zhoukou 466001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoyin","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou 466001, China"},{"name":"Fuxi Laboratory, Zhoukou Normal University, Zhoukou 466001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1699-8760","authenticated-orcid":false,"given":"Huazhen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9196-8532","authenticated-orcid":false,"given":"Changjing","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou 466001, China"},{"name":"Fuxi Laboratory, Zhoukou Normal University, Zhoukou 466001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/s41582-024-00940-4","article-title":"Is Alzheimer Disease a Disease?","volume":"20","author":"Korczyn","year":"2024","journal-title":"Nat. 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