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.
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Data Availability
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
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Funding
This work was supported by the Medical Science Research Project of Hebei Provincial Health Commission (Grant No. 20200872).
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Ya Gao, Shuyue Li, and Yidan Zhang performed the research; Jian Zhang, Yuan Zhao, Cui Chang, and Xuan Gao performed the data analysis and plotted figures; Ya Gao and Shuyue Li wrote the paper; Guofeng Yang conceived the study and revised the manuscript.
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The experiments were carried out in accordance with the regulations of laboratory animal management of the Ministry of Science and Technology of the People’s Republic of China and were approved by the Ethics Committee of the Second Hospital of Hebei Medical University.
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Gao, Y., Li, S., Zhang, Y. et al. 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. Neurotox Res 40, 1802–1811 (2022). https://doi.org/10.1007/s12640-022-00585-5
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DOI: https://doi.org/10.1007/s12640-022-00585-5