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Currently, multiple therapeutic strategies are being developed to design effective anti-AD drugs. Among them, Withaferin A (WA), a natural steroidal lactone extracted from Withania somnifera leaves, has been shown to reduce amyloid-\u03b2 (A\u03b2) peptide levels in vitro. However, its potential to improve cognitive function in AD remains unclear. Methods: In this study, 5xFAD mice were administered WA (2 mg\/kg intraperitoneally every 2 days) for 14 days, and its neuroprotective effects were evaluated through behavioral tests, wide-field imaging, immunohistochemistry, and ELISA. Results: WA significantly improved short-term memory, as evidenced by enhanced performance in the Novel Object Recognition Test (NORT) (p &lt; 0.001, n = 10), Novel Location Recognition Test (NLRT) (p &lt; 0.01, n = 14), and Three-Chamber Social Test (TCST) (p &lt; 0.001, n = 8). WA also ameliorated long-term memory deficits in the Morris Water Maze Test (MWMT) (p &lt; 0.05, n = 7). Furthermore, cortical wide-field Ca2+ imaging revealed that WA treatment rescued slow-wave impairments by enhancing long-range coherence (0.8363 \u00b1 0.0185, p &lt; 0.01, n = 8) and reducing the frequency of slow-wave activity (0.6578 \u00b1 0.0512 Hz, p &lt; 0.01, n = 8). Additionally, WA treatment significantly reduced A\u03b2 plaque deposition in both cortical and hippocampal regions. Conclusions: These findings suggest that WA may be a promising therapeutic agent for AD, exerting neuroprotective effects.<\/jats:p>","DOI":"10.3390\/ph18060816","type":"journal-article","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T06:25:04Z","timestamp":1748499904000},"page":"816","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Withaferin A Rescues Brain Network Dysfunction and Cognitive Deficits in a Mouse Model of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"18","author":[{"given":"Linhan","family":"Yang","sequence":"first","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine\/Advanced Institute for Brain and Intelligence, School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2328-7066","authenticated-orcid":false,"given":"Yang","family":"Zou","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine\/Advanced Institute for Brain and Intelligence, School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihua","family":"Fan","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine\/Advanced Institute for Brain and Intelligence, School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pu","family":"Yin","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine\/Advanced Institute for Brain and Intelligence, School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Qin","sequence":"additional","affiliation":[{"name":"LFC Laboratory and Chongqing Institute for Brain and Intelligence, Guangyang Bay Laboratory, Chongqing 400064, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Li","sequence":"additional","affiliation":[{"name":"College of Intelligence Science and Technology, National University of Defense Technology, Changsha 410073, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengjuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Lanzhou University, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9028-1648","authenticated-orcid":false,"given":"Xingyi","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Neurointelligence, School of Medicine, Chongqing University, Chongqing 400044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaijin","family":"Teng","sequence":"additional","affiliation":[{"name":"LFC Laboratory and Chongqing Institute for Brain and Intelligence, Guangyang Bay Laboratory, Chongqing 400064, China"},{"name":"Brainspace Research Unit, Chongqing 400064, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Chen","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine\/Advanced Institute for Brain and Intelligence, School of Medicine, Guangxi University, Nanning 530004, China"},{"name":"LFC Laboratory and Chongqing Institute for Brain and Intelligence, Guangyang Bay Laboratory, Chongqing 400064, China"},{"name":"Brain Research Center and State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University, Chongqing 400038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunny C.","family":"Li","sequence":"additional","affiliation":[{"name":"LFC Laboratory and Chongqing Institute for Brain and Intelligence, Guangyang Bay Laboratory, Chongqing 400064, China"},{"name":"NewLight Neuroscience Unit, Chongqing 400064, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Logie, E., and Vanden Berghe, W. 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