Age-dependent decline in remyelination capacity is mediated by apelin-APJ signaling
Age-dependent decline in remyelination capacity is mediated by apelin-APJ signaling
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DOI：
10.1038/s43587-021-00041-7
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发表时间：
2021-03-01
期刊：
影响因子：
--
通讯作者：
Yamashita, Toshihide
中科院分区：
文献类型：
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作者：
Ito, Masumi;Muramatsu, Rieko;Yamashita, Toshihide
由于髓鞘再生效率下降，中枢神经系统可能会发生与年龄相关的再生衰竭。髓鞘形成细胞对再髓鞘形成信号的反应性受到与衰老相关的表观遗传学修饰的影响；然而，其分子机制尚未完全阐明。在本研究中，我们报道了apelin受体(APJ)介导的再髓鞘形成效率随年龄的变化。APJ在髓鞘形成细胞中的表达与年龄相关的再髓鞘形成效率的变化相关，APJ的激活通过髓鞘调节因子的移位促进再髓鞘形成。APJ信号激活促进了毒素诱导的脱髓鞘老龄小鼠和实验性自身免疫性脑脊髓炎小鼠的重新髓鞘形成。在人类细胞中，APJ激活增强了重新髓鞘形成标记物的表达。老年动物受损的少突胶质细胞功能可以可逆地重新激活；因此，结果表明APELIN-APJ系统的功能障碍介导了老年动物的再髓鞘失败，其髓鞘功能可以通过激活APJ来重新激活。研究表明，由于apelin受体APJ表达减少，衰老大脑中的再生受到损害。循环中的apelin通过APJ向少突胶质细胞发出信号以支持重新髓鞘形成，这一途径可以在使用APJ激动剂的老年小鼠中恢复。
Age-related regeneration failure in the central nervous system can occur as a result of a decline in remyelination efficacy. The responsiveness of myelin-forming cells to signals for remyelination is affected by aging-related epigenetic modification; however, the molecular mechanism is not fully clarified. In the present study, we report that the apelin receptor (APJ) mediates remyelination efficiency with age. APJ expression in myelin-forming cells is correlated with age-associated changes in remyelination efficiency, and the activation of APJ promotes remyelination through the translocation of myelin regulatory factor. APJ signaling activation promoted remyelination in both aged mice with toxin-induced demyelination and mice with experimental autoimmune encephalomyelitis. In human cells, APJ activation enhanced the expression of remyelination markers. Impaired oligodendrocyte function in aged animals can be reversibly reactivated; thus, the results demonstrate that dysfunction of the apelin-APJ system mediates remyelination failure in aged animals, and that their myelinating function can be reactivated by APJ activation.Ito et al. show that regeneration in the aging brain is impaired due to reduced expression of the apelin receptor APJ. Circulating apelin signals oligodendrocytes via APJ to support remyelination, and this pathway can be restored in older mice with an APJ agonist.