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Retinoid X Receptor Activation Reverses Age-Related Deficiencies in Myelin Debris Phagocytosis and Remyelination

Retinoid X Receptor Activation Reverses Age-Related Deficiencies in Myelin Debris Phagocytosis and Remyelination

Muktha S Natrajan, Alerie G de la Fuente, Abbe H Crawford, Eimear Linehan, Vanessa Nuñez, Kory R Johnson, Tianxia Wu, Denise C Fitzgerald, Mercedes Ricote, Bibiana Bielekova, Robin J M Franklin

Brain. 2015 Dec;138(Pt 12):3581-97.

PMID: 26463675

Abstract:

The efficiency of central nervous system remyelination declines with age. This is in part due to an age-associated decline in the phagocytic removal of myelin debris, which contains inhibitors of oligodendrocyte progenitor cell differentiation. In this study, we show that expression of genes involved in the retinoid X receptor pathway are decreased with ageing in both myelin-phagocytosing human monocytes and mouse macrophages using a combination of in vivo and in vitro approaches. Disruption of retinoid X receptor function in young macrophages, using the antagonist HX531, mimics ageing by reducing myelin debris uptake. Macrophage-specific RXRα (Rxra) knockout mice revealed that loss of function in young mice caused delayed myelin debris uptake and slowed remyelination after experimentally-induced demyelination. Alternatively, retinoid X receptor agonists partially restored myelin debris phagocytosis in aged macrophages. The agonist bexarotene, when used in concentrations achievable in human subjects, caused a reversion of the gene expression profile in multiple sclerosis patient monocytes to a more youthful profile and enhanced myelin debris phagocytosis by patient cells. These results reveal the retinoid X receptor pathway as a positive regulator of myelin debris clearance and a key player in the age-related decline in remyelination that may be targeted by available or newly-developed therapeutics.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP188844340	HX531		188844-34-0	Price

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