Age-dependent decline in remyelination capacity is mediated by apelin-APJ signaling

Age-related remyelination failure can occur as a result of a decline in the differentiation efficacy of oligodendrocytes. The responsiveness of oligodendrocytes to differentiation signals is affected by intrinsic aging-related changes; however, it remains unclear which molecular system regulates oligodendrocyte differentiation. Here, we report that apelin receptor (APJ) mediates oligodendrocyte differentiation efficiency with age, and that APJ expression is correlated with age-associated changes in differentiation efficiency. The activation of APJ promotes oligodendrocyte differentiation through the translocation of myelin regulatory factor (Myrf). Oligodendrocyte-specific APJ (aplnr)-knockout mice showed hypomyelination and motor dysfunction. Moreover, APJ signaling activation promoted remyelination both in aged mice with toxin-induced demyelination and in mice with experimental autoimmune encephalomyelitis. Additionally, in human cells, APJ activation enhanced the expression of oligodendrocyte differentiation markers. Impaired oligodendrocyte function in aged animals can be reversibly reactivated; thus, our findings suggest that the apelin-APJ system promotes central nervous system function in aged animals by reversibly reactivating impaired oligodendrocyte function.