The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD miceResearch in context
Summary: Background: 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...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396423002785 |
| _version_ | 1797745945928007680 |
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| author | Zhihui Zhu Liping Zhang Ahmed Elsherbini Simone M. Crivelli Priyanka Tripathi Carmen Harper Zainuddin Quadri Stefka D. Spassieva Erhard Bieberich |
| author_facet | Zhihui Zhu Liping Zhang Ahmed Elsherbini Simone M. Crivelli Priyanka Tripathi Carmen Harper Zainuddin Quadri Stefka D. Spassieva Erhard Bieberich |
| author_sort | Zhihui Zhu |
| collection | DOAJ |
| description | Summary: Background: 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. Methods: 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. Findings: 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. Interpretation: Ponesimod targeting S1PR1 is a promising therapeutic approach to reprogram microglia, reduce neuroinflammation, and increase Aβ clearance in AD. Funding: NIH R01AG064234, RF1AG078338, R21AG078601, VA I01BX003643. |
| first_indexed | 2024-03-12T15:30:08Z |
| format | Article |
| id | doaj.art-07d8ebe074684c7b8be23fb664553313 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-03-12T15:30:08Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-07d8ebe074684c7b8be23fb6645533132023-08-10T04:34:33ZengElsevierEBioMedicine2352-39642023-08-0194104713The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD miceResearch in contextZhihui Zhu0Liping Zhang1Ahmed Elsherbini2Simone M. Crivelli3Priyanka Tripathi4Carmen Harper5Zainuddin Quadri6Stefka D. Spassieva7Erhard Bieberich8Department of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536, United StatesDepartment of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536, United StatesDepartment of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536, United StatesDepartment of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536, United StatesDepartment of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536, United StatesDepartment of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536, United StatesDepartment of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536, United StatesDepartment of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536, United StatesDepartment of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536, United States; Veterans Affairs Medical Center, Lexington, KY 40502, United States; Corresponding author. Department of Physiology, College of Medicine, University of Kentucky, 780 Rose Street MS519, Lexington, KY 40536, United States.Summary: Background: 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. Methods: 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. Findings: 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. Interpretation: Ponesimod targeting S1PR1 is a promising therapeutic approach to reprogram microglia, reduce neuroinflammation, and increase Aβ clearance in AD. Funding: NIH R01AG064234, RF1AG078338, R21AG078601, VA I01BX003643.http://www.sciencedirect.com/science/article/pii/S2352396423002785Alzheimer's diseaseSphingosine-1-phosphateNeuroinflammationPonesimodToll-like receptor 4Phagocytosis |
| spellingShingle | Zhihui Zhu Liping Zhang Ahmed Elsherbini Simone M. Crivelli Priyanka Tripathi Carmen Harper Zainuddin Quadri Stefka D. Spassieva Erhard Bieberich The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD miceResearch in context EBioMedicine Alzheimer's disease Sphingosine-1-phosphate Neuroinflammation Ponesimod Toll-like receptor 4 Phagocytosis |
| title | The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD miceResearch in context |
| title_full | The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD miceResearch in context |
| title_fullStr | The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD miceResearch in context |
| title_full_unstemmed | The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD miceResearch in context |
| title_short | The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD miceResearch in context |
| title_sort | s1p receptor 1 antagonist ponesimod reduces tlr4 induced neuroinflammation and increases aβ clearance in 5xfad miceresearch in context |
| topic | Alzheimer's disease Sphingosine-1-phosphate Neuroinflammation Ponesimod Toll-like receptor 4 Phagocytosis |
| url | http://www.sciencedirect.com/science/article/pii/S2352396423002785 |
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