Agaricus blazei extract FA-2b-β inhibits microglial pyroptosis by regulating the activation of the NF-κB signaling pathway mediated by Aβ 1-42 through the NLRP3 pathway

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Intracellular neurofibrillary tangles (NFTs) and neuroinflammatory plaques formed by amyloid-β (Aβ) are the main pathological features of AD. FA-2b-β, a selenium mushroom extract from Qinba, had strong anti-inflammatory activity and could protect against various inflammatory diseases by regulating multiple signaling pathways. However, whether FA-2b-β can modulate Aβ ₁₋₄₂ -mediated neuroinflammation by inhibiting the NF-κB signaling pathway has not been systematically investigated. The present study aimed to explore the effect and mechanism of action of FA-2b-β on Aβ ₁₋₄₂ -mediated microglia inflammation. The results showed that FA-2b-β reduced Aβ ₁₋₄₂ -mediated release of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and the expression of key proteins of NF-κB signaling pathway TLR4 and p-IκB-α, and NLRP3 Inflammasome associated with NLRP3 and Caspase1. However, activation of the NF-κB signaling pathway activates NLRP3 inflammasome and leads to increased expression of pyroptosis key protein GSDMD. Further, knockout of NLRP3 and FA-2b-β intervention, respectively, in BV2 cells resulted in a corresponding reduction in the levels of inflammatory mediators, including NLRP3, Casp1, ASC, TNF-α, and IL-1β. Mechanistically, FA-2b-β inhibited activation of nuclear factor kappa B (NF-κB) and downregulated the Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) protein expression to suppress pyroptosis of BV2 cells. These findings suggested that FA-2b-β might represent a potential therapeutic agent for anti-neuroinflammation.