Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, USA.
Nature. 2022 May;605(7910):509-515. doi: 10.1038/s41586-022-04722-0. Epub 2022 May 11.
Recent understanding of how the systemic environment shapes the brain throughout life has led to numerous intervention strategies to slow brain ageing. Cerebrospinal fluid (CSF) makes up the immediate environment of brain cells, providing them with nourishing compounds. We discovered that infusing young CSF directly into aged brains improves memory function. Unbiased transcriptome analysis of the hippocampus identified oligodendrocytes to be most responsive to this rejuvenated CSF environment. We further showed that young CSF boosts oligodendrocyte progenitor cell (OPC) proliferation and differentiation in the aged hippocampus and in primary OPC cultures. Using SLAMseq to metabolically label nascent mRNA, we identified serum response factor (SRF), a transcription factor that drives actin cytoskeleton rearrangement, as a mediator of OPC proliferation following exposure to young CSF. With age, SRF expression decreases in hippocampal OPCs, and the pathway is induced by acute injection with young CSF. We screened for potential SRF activators in CSF and found that fibroblast growth factor 17 (Fgf17) infusion is sufficient to induce OPC proliferation and long-term memory consolidation in aged mice while Fgf17 blockade impairs cognition in young mice. These findings demonstrate the rejuvenating power of young CSF and identify Fgf17 as a key target to restore oligodendrocyte function in the ageing brain.
最近对全身环境如何在整个生命周期中塑造大脑的认识，催生了许多干预策略来减缓大脑衰老。脑脊液（CSF）构成了脑细胞的直接环境，为它们提供营养物质。我们发现，将年轻的 CSF 直接注入衰老的大脑中，可以改善记忆功能。对海马体的无偏转录组分析表明，少突胶质细胞对这种年轻化的 CSF 环境最为敏感。我们进一步表明，年轻的 CSF 可促进衰老海马体和原代少突胶质前体细胞（OPC）中的 OPC 增殖和分化。通过使用 SLAMseq 对新生 mRNA 进行代谢标记，我们发现血清反应因子（SRF），一种驱动肌动蛋白细胞骨架重排的转录因子，是 OPC 在接触年轻 CSF 后增殖的介质。随着年龄的增长，海马体 OPC 中的 SRF 表达减少，该途径可被急性注射年轻 CSF 诱导。我们在 CSF 中筛选潜在的 SRF 激活剂，发现成纤维细胞生长因子 17（Fgf17）的输注足以诱导衰老小鼠的 OPC 增殖和长期记忆巩固，而 Fgf17 阻断则会损害年轻小鼠的认知能力。这些发现表明年轻 CSF 具有年轻化的力量，并确定 Fgf17 是恢复衰老大脑中少突胶质细胞功能的关键靶点。
