Withaferin A Rescues Brain Network Dysfunction and Cognitive Deficits in a Mouse Model of Alzheimer’s Disease

<b>Background:</b> Alzheimer's disease (AD) is the most common dementia, characterized by significant cognitive impairments and neural network dysfunction. 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-β (Aβ) peptide levels in vitro. However, its potential to improve cognitive function in AD remains unclear. <b>Methods:</b> 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. <b>Results:</b> WA significantly improved short-term memory, as evidenced by enhanced performance in the Novel Object Recognition Test (NORT) (<i>p</i> < 0.001, <i>n</i> = 10), Novel Location Recognition Test (NLRT) (<i>p</i> < 0.01, <i>n</i> = 14), and Three-Chamber Social Test (TCST) (<i>p</i> < 0.001, <i>n</i> = 8). WA also ameliorated long-term memory deficits in the Morris Water Maze Test (MWMT) (<i>p</i> < 0.05, <i>n</i> = 7). Furthermore, cortical wide-field Ca²⁺ imaging revealed that WA treatment rescued slow-wave impairments by enhancing long-range coherence (0.8363 ± 0.0185, <i>p</i> < 0.01, <i>n</i> = 8) and reducing the frequency of slow-wave activity (0.6578 ± 0.0512 Hz, <i>p</i> < 0.01, <i>n</i> = 8). Additionally, WA treatment significantly reduced Aβ plaque deposition in both cortical and hippocampal regions. <b>Conclusions:</b> These findings suggest that WA may be a promising therapeutic agent for AD, exerting neuroprotective effects.