The p300-NF-κB pathway induces the activation of the NLRP3 inflammasome and the pyroptosis of neurons in an in vitromodel of Alzheimer’s disease.

Inflammation-induced neuronal death is the primary cause of Alzheimer’s disease (AD). p300 plays an important role in brain disorders. How-ever, the role of p300 in AD remains unclear. This study aimed to investigate the potential of p300 in an in vitro model of AD. Protein expression was detected using western blotting. The mRNA levels were determined by reverse transcrip-tion-quantitative polymerase chain reaction. Cytokine release was detected us-ing an enzyme-linked immunosorbent assay. Cellular function was determined using the cell counting kit-8, lactate dehydrogenase, and flow cytometry assays. Chromatin immunoprecipitation and luciferase assays verified the interaction between nuclear factor kappa B (NF-κB) and the NLR family pyrin domain con-taining 3 (NLRP3). E1A binding protein p300 (p300) was overexpressed in the Aβ1-42 induced AD model in vitro. However, treatment with the p300 inhibitor (GNE-049) alleviated inflammation and Aβ1-42-induced pyroptosis in the neu-rons. p300 activates NF-κB, which antagonizes the effects of GNE-049 and pro-motes neuronal pyroptosis. Moreover, NF-κB epigenetically activates the NLRP3 inflammasome. The p300/NF-κB pathway promotes neuronal pyroptosis in an in vitro AD model by activating the NLRP3 inflammasome. Therefore, the p300/NF-κB/NLRP3 signalling pathway may be a potential therapeutic target for AD.