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

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. 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. WA significantly improved short-term memory, as evidenced by enhanced performance in the Novel Object Recognition Test (NORT) ( < 0.001, = 10), Novel Location Recognition Test (NLRT) ( < 0.01, = 14), and Three-Chamber Social Test (TCST) ( < 0.001, = 8). WA also ameliorated long-term memory deficits in the Morris Water Maze Test (MWMT) ( < 0.05, = 7). Furthermore, cortical wide-field Ca imaging revealed that WA treatment rescued slow-wave impairments by enhancing long-range coherence (0.8363 ± 0.0185, < 0.01, = 8) and reducing the frequency of slow-wave activity (0.6578 ± 0.0512 Hz, < 0.01, = 8). Additionally, WA treatment significantly reduced Aβ plaque deposition in both cortical and hippocampal regions. These findings suggest that WA may be a promising therapeutic agent for AD, exerting neuroprotective effects.