Brain aging is characterised by a decline in neuronal function and associated cognitive deficits. There is increasing evidence that myelin disruption is an important factor that contributes to the age-related loss of brain plasticity and repair responses. In the brain, myelin is produced by oligodendrocytes, which are generated throughout life by oligodendrocyte progenitor cells (OPCs). Currently, a leading hypothesis points to aging as a major reason for the ultimate breakdown of remyelination in Multiple Sclerosis (MS). However, an incomplete understanding of the cellular and molecular processes underlying brain aging hinders the development of regenerative strategies. Here, our combined systems biology and neurobiological approach demonstrates that oligodendroglial and myelin genes are amongst the most altered in the aging mouse cortex. This was underscored by the identification of causal links between signaling pathways and their downstream transcriptional networks that define oligodendroglial disruption in aging. The results highlighted that the G-protein coupled receptor GPR17 is central to the disruption of OPC in aging and this was confirmed by genetic fate mapping and cellular analyses. Finally, we used systems biology strategies to identify therapeutic agents that rejuvenate OPC and restore myelination in age-related neuropathological contexts.

中文翻译：

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功能基因组学分析突显了少突胶质细胞祖细胞（OPC）中Gpr17调控的细胞过程的转变以及老年前脑的潜在髓磷脂失调

脑衰老的特征是神经元功能下降和相关的认知缺陷。越来越多的证据表明，髓磷脂破坏是导致与年龄相关的大脑可塑性和修复反应丧失的重要因素。在大脑中，髓磷脂是由少突胶质细胞产生的，少突胶质细胞是一生中由少突胶质细胞祖细胞（OPC）产生的。当前，一个主要的假设指出衰老是多发性硬化症（MS）中髓鞘再生最终破裂的主要原因。然而，对大脑衰老背后的细胞和分子过程的不完全了解阻碍了再生策略的发展。在这里，我们结合的系统生物学和神经生物学方法证明，少突胶质和髓磷脂基因在衰老的小鼠皮层中变化最大。通过确定信号传导途径与其下游转录网络之间的因果联系来强调这一点，这些联系定义了衰老中的少突胶质细胞破坏。结果强调，G蛋白偶联受体GPR17是衰老过程中OPC破坏的关键，这一点已通过遗传命运图谱和细胞分析得到证实。最后，我们使用系统生物学策略来鉴定在年龄相关的神经病理学背景下能使OPC焕发活力并恢复髓鞘形成的治疗剂。结果强调，G蛋白偶联受体GPR17是衰老过程中OPC破坏的关键，这一点已通过遗传命运图谱和细胞分析得到证实。最后，我们使用系统生物学策略来鉴定在年龄相关的神经病理学背景下能使OPC焕发活力并恢复髓鞘形成的治疗剂。结果强调，G蛋白偶联受体GPR17是衰老过程中OPC破坏的关键，这一点已通过遗传命运图谱和细胞分析得到证实。最后，我们使用系统生物学策略来鉴定在年龄相关的神经病理学背景下能使OPC焕发活力并恢复髓鞘形成的治疗剂。