Polydatin Attenuates Cognitive Deficits and Neuroinflammation by Inhibiting the P2X7/NLRP1 Inflammasome Pathway in APP/PS1 Mice and Aβ-Treated HT22 Cells.

Aβ deposition is a central pathological hallmarks of Alzheimer's disease (AD), contributing to oxidative stress, neuroinflammation, and neuronal pyroptosis. Polydatin (PD) is a natural polyphenolic compound with known anti-inflammatory and antioxidant properties, has been rarely studied in the context of AD. This study aims to investigate the neuroprotective effects and underlying mechanisms of PD in APP/PS1 transgenic mice and Aβ25-35-treated HT22 cells. Spatial exploration experiments indicate that PD administration (200 mg/kg/day) attenuated cognitive deficits. Histopathological analyses, including hematoxylin-eosin staining and transmission electron microscopy, revealed that PD mitigated hippocampal structural damage in APP/PS1 mice. Western blot and RT-qPCR results showed that PD markedly reduced the expression of pyroptosis-related proteins, including P2X7, NLRP1, ASC, caspase-1, and GSDMD, as well as oxidative stress markers in the hippocampus. In vitro, Aβ₂₅-₃₅ exposure led to an increased expression of P2X7 and components of the NLRP1 inflammasome in HT22 cells, which was reversed by PD treatment. What's more, siRNA knockdown experiments revealed that silencing P2X7 significantly downregulated NLRP1, whereas siNLRP1 had no significant effect on P2X7 expression, suggesting that P2X7 functions upstream of NLRP1. These findings indicate that PD alleviates AD-like pathology by suppressing P2X7/NLRP1 inflammasome-mediated pyroptosis, highlighting its potential as a multi-target therapeutic candidate for AD intervention.