Abstract
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.
Original language | English |
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Article number | 104713 |
Journal | EBioMedicine |
Volume | 94 |
DOIs | |
State | Published - Aug 2023 |
Bibliographical note
Funding Information:The authors acknowledge funding by NIH grants R01AG064234 , RF1AG078338 , R21AG078601 , and VA grant I01BX003643 . We thank Dr. Guanghu Wang for starting, obtaining the initial funding for, and advising on this study and assistance with acquiring the BV2 cells. We thank the Department of Physiology (Chair Dr. Alan Daugherty) at the University of Kentucky , Lexington, KY for institutional support.
Funding Information:
NIH R01AG064234, RF1AG078338, R21AG078601, VA I01BX003643.The authors acknowledge funding by NIH grants R01AG064234, RF1AG078338, R21AG078601, and VA grant I01BX003643. We thank Dr. Guanghu Wang for starting, obtaining the initial funding for, and advising on this study and assistance with acquiring the BV2 cells. We thank the Department of Physiology (Chair Dr. Alan Daugherty) at the University of Kentucky, Lexington, KY for institutional support.
Publisher Copyright:
© 2023
Keywords
- Alzheimer's disease
- Neuroinflammation
- Phagocytosis
- Ponesimod
- Sphingosine-1-phosphate
- Toll-like receptor 4
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology (all)