Cui Weigang, Sun Chunli, Ma Yuqi, Wang Songtao, Wang Xianwei, Zhang Yinghua
Department of Human Anatomy, Xinxiang Medical University, Xinxiang, China.
Xinxiang Key Laboratory of Molecular Neurology, Xinxiang Medical University, Xinxiang, China.
Front Neurosci. 2020 May 20;14:444. doi: 10.3389/fnins.2020.00444. eCollection 2020.
Accumulating evidence has indicated that activation of microglia and neuroinflammation reaction play a prominent role in Alzheimer's disease (AD). Inhibition of toll-like receptor 4 (TLR4) has been shown to be associated with immune responses and brain damage, but its effects on AD remain unclear. This study mainly aimed to investigate the protective effect of TAK-242 (TLR4-specific inhibitor) on microglial polarization and neuroprotection in an AD mouse model and the underlying mechanisms. We found that APP/PS1 transgenic AD mice exhibited a dramatic increase in TLR4 levels concomitant with a significantly higher expression of inflammatory microglia compared to C57BL/6 wild-type mice. Furthermore, inhibition of TLR4 by TAK-242 administration significantly improved neurological function, decreased the level of Bax, and caused a significant reduction in the levels of M1-markers (iNOS and TNFα), while the expressions of M2-phenotype markers (Trem-2 and Arg-1) were increased both and . Furthermore, TAK-242 treatment enhanced BV2 microglial phagocytosis. Moreover, Aβ caused the upregulation of inflammatory cytokine production, MyD88, NF-kappaB-p65, and NLRP3, which could be ameliorated by NLRP3-siRNA or TAK-242. These findings indicated that TLR4 inhibition provided neuroprotection and promoted a microglial switch from the inflammatory M1 phenotype to the protective M2 phenotype in AD. The mechanism involved may be related to modulation of the MyD88/NF-kappaB/NLRP3 signaling pathway.
越来越多的证据表明，小胶质细胞的激活和神经炎症反应在阿尔茨海默病（AD）中起着重要作用。已有研究表明，抑制Toll样受体4（TLR4）与免疫反应和脑损伤有关，但其对AD的影响仍不清楚。本研究主要旨在探讨TAK-242（TLR4特异性抑制剂）对AD小鼠模型中小胶质细胞极化和神经保护的作用及其潜在机制。我们发现，与C57BL/6野生型小鼠相比，APP/PS1转基因AD小鼠的TLR4水平显著升高，同时炎症小胶质细胞的表达也显著增加。此外，给予TAK-242抑制TLR4可显著改善神经功能，降低Bax水平，并显著降低M1标记物（诱导型一氧化氮合酶和肿瘤坏死因子α）的水平，而M2表型标记物（触发受体表达分子2和精氨酸酶1）的表达在[具体情况未提及的两个方面]均增加。此外，TAK-242处理增强了BV2小胶质细胞的吞噬作用。此外，淀粉样β蛋白（Aβ）导致炎症细胞因子产生、髓样分化因子88（MyD88）、核因子κB p65（NF-κB-p65）和NLR家族含pyrin结构域蛋白3（NLRP3）上调，而NLRP3小干扰RNA（NLRP3-siRNA）或TAK-242可改善这种情况。这些发现表明，抑制TLR4可提供神经保护，并促进AD中小胶质细胞从炎症性M1表型向保护性M2表型转变。其涉及的机制可能与MyD88/NF-κB/NLRP3信号通路的调节有关。
