{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:11:47Z","timestamp":1790881907443,"version":"4.1.0"},"reference-count":62,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2024,10,20]],"date-time":"2024-10-20T00:00:00Z","timestamp":1729382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["52072360"],"award-info":[{"award-number":["52072360"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["62305347"],"award-info":[{"award-number":["62305347"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Nature Science Research Project of Anhui province","award":["2208085MB31"],"award-info":[{"award-number":["2208085MB31"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Alzheimer\u2019s disease (AD) is a common clinical neurodegenerative disorder, primarily characterized by progressive cognitive decline and behavioral abnormalities. The hallmark pathological changes of AD include widespread neuronal degeneration, plaques formed by the deposition of amyloid \u03b2-protein (A\u03b2), and neurofibrillary tangles (NFTs). With the acceleration of global aging, the incidence of AD is rising year by year, making it a major global public health concern. Due to the complex pathology of AD, finding effective interventions has become a key focus of research. Ouabain (OUA), a cardiac glycoside, is well-known for its efficacy in treating heart disease. Recent studies have also indicated its potential in AD therapy, although its exact mechanism of action remains unclear. Methods: This study integrates bioinformatics, multi-omics technologies, and in vivo and in vitro experiments to investigate the effects of OUA on the pathophysiological changes of AD and its underlying molecular mechanisms. Results: This study analyzed the expression of the triggering receptor expressed on myeloid cells 2 (TREM2) across different stages of AD using bioinformatics. Serum samples from patients were used to validate soluble TREM2 (sTREM2) levels. Using an A\u03b21-42-induced microglial cell model, we confirmed that OUA enhances the PI3K\/AKT signaling pathway activation by upregulating TREM2, which reduces neuroinflammation and promotes the transition of microglia from an M1 proinflammatory state to an M2 anti-inflammatory state. To evaluate the in vivo effects of OUA, we assessed the learning and memory capacity of FAD4T transgenic mice using the Morris water maze and contextual fear conditioning tests. We used real-time quantitative PCR, immunohistochemistry, and Western blotting to measure the expression of inflammation-associated cytokines and to assess microglia polarization. OUA enhances cognitive function in FAD4T mice and has been confirmed to modulate microglial M1\/M2 phenotypes both in vitro and in vivo. Furthermore, through bioinformatics analysis, molecular docking, and experimental validation, TREM2 was identified as a potential target for OUA. It regulates PI3K\/Akt signaling pathway activation, playing a crucial role in OUA-mediated M2 microglial polarization and its anti-inflammatory effects in models involving A\u03b21-42-stimulated BV-2 cells and FAD4T mice. Conclusions: These findings indicate that OUA exerts anti-neuroinflammatory effects by regulating microglial polarization, reducing the production of inflammatory mediators, and activating the PI3K\/Akt signaling pathway. Given its natural origin and dual effects on microglial polarization and neuroinflammation, OUA emerges as a promising therapeutic candidate for neuroinflammatory diseases such as AD.<\/jats:p>","DOI":"10.3390\/nu16203558","type":"journal-article","created":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T08:53:11Z","timestamp":1729500791000},"page":"3558","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Ouabain Ameliorates Alzheimer\u2019s Disease-Associated Neuropathology and Cognitive Impairment in FAD4T Mice"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-0384-1621","authenticated-orcid":false,"given":"Dan","family":"Wang","sequence":"first","affiliation":[{"name":"Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China"},{"name":"Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei 230001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qizhi","family":"Zhu","sequence":"additional","affiliation":[{"name":"The Science Island Branch of Graduate School, University of Science and Technology of China, Hefei 230026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wei","sequence":"additional","affiliation":[{"name":"The Science Island Branch of Graduate School, University of Science and Technology of China, Hefei 230026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Tang","sequence":"additional","affiliation":[{"name":"Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiping","family":"Xu","sequence":"additional","affiliation":[{"name":"Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China"},{"name":"Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei 230001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1016\/S0140-6736(10)61349-9","article-title":"Alzheimer\u2019s disease","volume":"377","author":"Ballard","year":"2011","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1038\/475S1a","article-title":"Alzheimer\u2019s disease","volume":"475","author":"Brody","year":"2011","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"559","DOI":"10.2174\/1567205016666190321154618","article-title":"Systemic and CNS Inflammation Crosstalk: Implications for Alzheimer\u2019s Disease","volume":"16","author":"Paouri","year":"2019","journal-title":"Curr. 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