| First Author | Zhu Z | Year | 2023 |
| Journal | EBioMedicine | Volume | 94 |
| Pages | 104713 | PubMed ID | 37480622 |
| Mgi Jnum | J:339126 | Mgi Id | MGI:7515314 |
| Doi | 10.1016/j.ebiom.2023.104713 | Citation | Zhu Z, et al. (2023) The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Abeta clearance in 5XFAD mice. EBioMedicine 94:104713 |
| abstractText | BACKGROUND: Previously, we showed that the sphingosine-1-phosphate (S1P) transporter spinster 2 (Spns2) mediates activation of microglia in response to amyloid beta peptide (Abeta). Here, we investigated if Ponesimod, a functional S1P receptor 1 (S1PR1) antagonist, prevents Abeta-induced activation of glial cells and Alzheimer's disease (AD) pathology. METHODS: We used primary cultures of glial cells and the 5XFAD mouse model to determine the effect of Abeta and Ponesimod on glial activation, Abeta phagocytosis, cytokine levels and pro-inflammatory signaling pathways, AD pathology, and cognitive performance. FINDINGS: Abeta(42) 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 Abeta(42) in primary cultured microglia. In 5XFAD mice, Ponesimod decreased the levels of TNF-alpha and CXCL10, which activate TLR4 and Stat1. It also increased the level of IL-33, an anti-inflammatory cytokine that promotes Abeta(42) 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. INTERPRETATION: Ponesimod targeting S1PR1 is a promising therapeutic approach to reprogram microglia, reduce neuroinflammation, and increase Abeta clearance in AD. FUNDING: NIHR01AG064234, RF1AG078338, R21AG078601, VAI01BX003643. |
