The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD mice.
The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD mice.
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DOI：
10.1016/j.ebiom.2023.104713
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发表时间：
2023-08
期刊：
影响因子：
11.1
通讯作者：
Bieberich, Erhard
中科院分区：
文献类型：
--
作者：
Zhu, Zhihui;Zhang, Liping;Elsherbini, Ahmed;Crivelli, Simone M.;Tripathi, Priyanka;Harper, Carmen;Quadri, Zainuddin;Spassieva, Stefka D.;Bieberich, Erhard
关键词：
以前，我们发现鞘氨醇-1-磷酸（S1 P）转运蛋白spinster 2（Spns 2）介导小胶质细胞对淀粉样β肽（Aβ）的激活。在这里，我们研究了Ponesimod，一种功能性S1 P受体1（S1 PR 1）拮抗剂，是否能阻止Aβ诱导的胶质细胞活化和阿尔茨海默病（AD）病理学。我们使用神经胶质细胞的原代培养物和5XFAD小鼠模型来确定Aβ和Ponesimod对神经胶质活化、Aβ吞噬作用、细胞因子水平和促炎信号传导途径、AD病理学和认知表现的影响。Aβ42增加TLR 4和S1 PR 1的水平，导致它们的复合物形成。Ponesimod阻止了TLR 4和S1 PR 1水平的增加，以及它们复合物的形成。它还减少了促炎性Stat 1和p38 MAPK信号通路的激活，同时激活了抗炎性Stat 6通路。这与原代培养的小胶质细胞中Aβ42的吞噬作用增加一致。在5XFAD小鼠中，Ponesimod降低了TNF-α和CXCL 10的水平，这两种物质激活了TLR 4和Stat 1。它还增加了IL-33的水平，IL-33是一种抗炎细胞因子，可促进小胶质细胞吞噬Aβ42。作为这些变化的结果，Ponesimod减少了Iba-1+小胶质细胞和GFAP+星形胶质细胞的数量，以及淀粉样蛋白斑块的大小和数量，同时改善了Y-迷宫测试中测量的空间记忆。靶向S1 PR 1的Ponesimod是一种很有前途的治疗方法，可以重新编程小胶质细胞，减少神经炎症，并增加AD中的Aβ清除率。R01AG064234、RF1AG078338、R21AG078601、I01BX 003643。
Previously, we showed that the sphingosine-1-phosphate (S1P) transporter spinster 2 (Spns2) mediates activation of microglia in response to amyloid β peptide (Aβ). Here, we investigated if Ponesimod, a functional S1P receptor 1 (S1PR1) antagonist, prevents Aβ-induced activation of glial cells and Alzheimer's disease (AD) pathology. We used primary cultures of glial cells and the 5XFAD mouse model to determine the effect of Aβ and Ponesimod on glial activation, Aβ phagocytosis, cytokine levels and pro-inflammatory signaling pathways, AD pathology, and cognitive performance. Aβ42 increased the levels of TLR4 and S1PR1, leading to their complex formation. Ponesimod prevented the increase in TLR4 and S1PR1 levels, as well as the formation of their complex. It also reduced the activation of the pro-inflammatory Stat1 and p38 MAPK signaling pathways, while activating the anti-inflammatory Stat6 pathway. This was consistent with increased phagocytosis of Aβ42 in primary cultured microglia. In 5XFAD mice, Ponesimod decreased the levels of TNF-α and CXCL10, which activate TLR4 and Stat1. It also increased the level of IL-33, an anti-inflammatory cytokine that promotes Aβ42 phagocytosis by microglia. As a result of these changes, Ponesimod decreased the number of Iba-1+ microglia and GFAP+ astrocytes, and the size and number of amyloid plaques, while improving spatial memory as measured in a Y-maze test. Ponesimod targeting S1PR1 is a promising therapeutic approach to reprogram microglia, reduce neuroinflammation, and increase Aβ clearance in AD. R01AG064234, RF1AG078338, R21AG078601, I01BX003643.
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DOI：
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