Cattle Encephalon Glycoside and Ignotin Attenuates Aβ1-42-Mediated Neurotoxicity by Preventing NLRP3 Inflammasome Activation and Modulating Microglial Polarization via TLR4/NF-κB Signaling Pathway

Abstract

The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation-mediated microglial polarization and chronic neuroinflammation play a crucial role in the process of Alzheimer's disease (AD). The previous study has shown that cattle encephalon glycoside and ignotin (CEGI) exerted an anti-inflammatory effect and inhibited inflammatory cytokines release by downregulating the Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) pathway in AD models. However, it is not clear whether CEGI can inhibit NLRP3 inflammasome activation and regulate the polarization of microglia in AD and whether its effects rely on TLR4/NF-κB signaling pathway. In the present study, we found that CEGI attenuated amyloid-β (Aβ)1-42-induced apoptosis, increased Aβ degrading enzymes (insulin-degrading enzyme and neprilysin), and promoted the clearance of Aβ1-42 in BV2 cells. CEGI also restrained the expression of NLRP3 and M1 microglial marker (inducible nitric oxide synthase) and elevated the expression of M2 microglial markers (arginase-1 and CD206). Meanwhile, knockdown of TLR4 with small interfering RNA proved that TLR4/NF-κB signaling was involved in the effects of CEGI. Furthermore, the roles of CEGI in inhibiting NLRP3 inflammasome activation, modulating microglia M1/M2 polarization, and increasing Aβ degrading enzyme expression were further validated in vivo using APP/PS1 mice. In conclusion, CEGI promotes Aβ degradation and protects microglia against Aβ1-42-induced neurotoxicity by preventing NLRP3 inflammasome activation and regulating M1/M2 polarization via TLR4/NF-κB pathways.

Keywords: Alzheimer’s disease; CEGI; Microglial polarization; NLRP3 inflammasome; TLR4.