Abstract
Multiple sclerosis (MS) is marked by neuroinflammation and demyelination with loss of oligodendrocytes in the central nervous system. The immune response is regulated by WNT/beta-catenin pathway in MS. Activated NF-kappaB, a major effector of neuroinflammation, and upregulated canonical WNT/beta-catenin pathway positively regulate each other. Demyelinating events present an upregulation of WNT/beta-catenin pathway, whereas proper myelinating phases show a downregulation of WNT/beta-catenin pathway essential for the promotion of oligodendrocytes precursors cells proliferation and differentiation. The activation of WNT/beta-catenin pathway results in differentiation failure and impairment in remyelination. However, PI3K/Akt pathway and TCF7L2, two downstream targets of WNT/beta-catenin pathway, are upregulated and promote proper remyelination. The interactions of these signaling pathways remain unclear. PPAR gamma activation can inhibit NF-kappaB, and can also downregulate the WNT/beta-catenin pathway. PPAR gamma and canonical WNT/beta-catenin pathway act in an opposite manner. PPAR gamma agonists appear as a promising treatment for the inhibition of demyelination and the promotion of proper remyelination through the control of both NF-kappaB activity and canonical WNT/beta-catenin pathway.
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Abbreviations
- APC:
-
Adenomatous polyposis coli
- DSH:
-
Disheveled
- FZD:
-
Frizzled
- GSK-3beta:
-
Glycogen synthase kinase-3beta
- LRP 5/6:
-
Low-density lipoprotein receptor-related protein 5/6
- PI3K-Akt:
-
Phosphatidylinositol 3-kinase-protein kinase B
- PPAR gamma:
-
Peroxisome proliferator-activated receptor gamma
- TCF/LEF:
-
T cell factor/lymphoid enhancer factor
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Acknowledgements
We would like to thank Dr Christophe Locher, President of the “Fédération de la Recherche Clinique du Grand Hôpital de l’Est Francilien,” and Mr. Vincent Gobert, Administrative Manager of the Clinical Research Center, Meaux Hospital, Meaux, France, for their valuable support in making the necessary research facilities available for this study.
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Vallée, A., Vallée, JN., Guillevin, R. et al. Interactions Between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma on Neuroinflammation, Demyelination, and Remyelination in Multiple Sclerosis. Cell Mol Neurobiol 38, 783–795 (2018). https://doi.org/10.1007/s10571-017-0550-9
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DOI: https://doi.org/10.1007/s10571-017-0550-9