PDF(Sci-hub)
Abstract：
Emerging evidence indicates that the enhancement of microglial autophagy inhibits the NLRP3 inflammasome mediated neuroinflammation in Alzheimer\'s disease (AD). Meanwhile, low density lipoprotein receptor-related protein 1 (LRP1) highly expressed in microglia is able to negatively regulate neuroinflammation and positively regulate autophagy. In addition, we have previously reported that an active lychee seed fraction enriching polyphenol (LSP) exhibits anti-neuroinflammation in Aβ-induced BV-2 cells. However, its molecular mechanism of action is still unclear. In this study, we aim to investigate whether LSP inhibits the NLRP3 inflammasome mediated neuroinflammation and clarify its molecular mechanism in Aβ-induced BV-2 cells and APP/PS1 mice. The results showed that LSP dose- and time-dependently activated autophagy by increasing the expression of Beclin 1 and LC3II in BV-2 cells, which was regulated by the upregulation of LRP1 and its mediated AMPK signaling pathway. In addition, both the Western blotting and fluorescence microscopic results demonstrated that LSP could significantly suppress the activation of NLRP3 inflammasome by inhibiting the expression of NLRP3, ASC, the cleavage of caspase-1, and the release of IL-1β in Aβ(1-42)-induced BV-2 cells. In addition, the siRNA LRP1 successfully abolished the effect of LSP on the activation of AMPK and its mediated autophagy, as well as the inhibition of NLRP3 inflammasome. Furthermore, LSP rescued PC-12 cells which were induced by the conditioned medium from Aβ(1-42)-treated BV-2 cells. Moreover, LSP improved the cognitive function and inhibited the NLRP3 inflammasome in APP/PS1 mice. Taken together, LSP inhibited the NLRP3 inflammasome-mediated neuroinflammation in the in vitro and in vivo models of AD, which was closely associated with the LRP1/AMPK-mediated autophagy. Thus, the findings from this study further provide evidences for LSP serving as a potential drug for the treatment of AD in the future.
摘要：
新的证据表明，小胶质细胞自噬的增强抑制了NLRP3炎性体介导的神经炎症在阿尔茨海默病（AD）中的作用。同时,在小胶质细胞中高表达的低密度脂蛋白受体相关蛋白1（LRP1）能够负调节神经炎症和正调节自噬。此外,我们以前报道过，富含多酚（LSP）的活性荔枝种子部分在Aβ诱导的BV-2细胞中表现出抗神经炎症。然而,其分子作用机制尚不清楚。在这项研究中,我们旨在研究LSP是否抑制NLRP3炎症小体介导的神经炎症，并阐明其在Aβ诱导的BV-2细胞和APP/PS1小鼠中的分子机制。结果表明，LSP通过增加BV-2细胞中Beclin1和LC3II的表达，剂量和时间依赖性地激活自噬，受LRP1上调及其介导的AMPK信号通路的调控。此外,Western印迹和荧光显微镜检测结果均表明LSP可以通过抑制NLRP3、ASC、Aβ（1-42）诱导的BV-2细胞中caspase-1的裂解和IL-1β的释放。此外,siRNALRP1成功地消除了LSP对AMPK激活及其介导的自噬的影响,以及对NLRP3炎性体的抑制作用。此外，LSP拯救了由条件培养基从Aβ(1-42)处理的BV-2细胞诱导的PC-12细胞。此外，LSP改善APP/PS1小鼠的认知功能并抑制NLRP3炎症小体。一起来看,LSP在AD的体外和体内模型中抑制NLRP3炎症小体介导的神经炎症，与LRP1/AMPK介导的自噬密切相关。因此，本研究的发现进一步为LSP作为未来治疗AD的潜在药物提供了证据.
