1,7-diphenyl-4-hepten-3-one mitigates Alzheimer's-like pathology by inhibiting pyroptosis via activating the Nrf2 pathway.

Pyroptosis-mediated neuron death plays a crucial role in neurodegenerative diseases, such as Alzheimer's disease (AD). However, the effect of 1,7-diphenyl-4-hepten-3-one (C1), a natural diarylheptanoid, on AD is unclear. Herein, we investigated the therapeutic effect of C1 on APP/PS1 mice and β-amyloid (Aβ)-induced HT22 cells. Our findings showed that C1 attenuated cognitive impairment and mitigated pathological damage in APP/PS1 mice. Furthermore, we found that C1 prevented oxidative stress damage and decreased the levels of pyroptosis-related proteins. In vitro experiments showed that C1 can improve the proliferation of Aβ-induced HT22 cells and decrease the levels of pyroptosis-related proteins in them. When Nrf2 was silenced, the positive effects of C1 in inhibiting pyroptosis were inhibited. Particularly, the production of pyroptosis-associated proteins, including NLRP3, GSDMD, and caspase-1, and the secretion of pro-inflammatory molecules, including IL-1 and IL-18, were increased. Altogether, these findings indicate that C1 can mitigate AD-like pathology via the inhibition of pyroptosis by activating the Nrf2 pathway. We believe that this study can provide alternative strategies for the prevention and treatment of AD.