FA-2-b-β modulates HMGB1/NF-κB/NLRP3 signaling to alleviate neuroinflammation in Alzheimer’s disease

Background FA-2-b-β, an extract derived from traditional Chinese medicine (TCM), has been suggested as a potential neuroprotective agent. Objective This study aimed to elucidate its role in modulating HMGB1-mediated inflammation and pyroptosis in Alzheimer's disease (AD), with a particular emphasis on the interaction between FA-2-b-β and HMGB1. Methods AD cell and animal models were used to examine the effect of FA-2-b-β on HMGB1/NF-κB/NLRP3 signaling pathway. Protein expression levels were detected by western blotting, and enzyme-linked immunosorbent assay (ELISA), respectively. Immunofluorescence staining was performed to determine the cellular localization of key proteins. The role of HMGB1 in amyloid-β (Aβ)-induced neuroinflammation and pyroptosis was examined through siRNA-mediated HMGB1 knockdown. Behavioral tests were conducted in AD animal models to evaluate cognitive improvements following FA-2-b-β treatment. Results In cellular models, FA-2-b-β significantly suppressed Aβ-induced overexpression HMGB1 and inhibited the activation of NF-κB, which consequently led to a reduction in the formation of the NLRP3 inflammasome. This suppression resulted in decreased of activation caspase-1 and lower levels of IL-1β and IL-18, thereby alleviating pyroptosis and neuroinflammation. The knockdown of HMGB1 further corroborated its role in mediating Aβ-induced inflammatory responses. In AD animal models, treatment with FA-2-b-β attenuated neuroinflammation, preserved neuronal integrity, and enhanced cognitive function. Conclusions FA-2-b-β exhibits a capacity to modulate the HMGB1/NF-κB/NLRP3 signaling pathway, thereby mitigating neuroinflammation and pyroptosis, highlighting its potential as a therapeutic intervention for AD.