Young CSF restores oligodendrogenesis and memory in aged mice via Fgf17

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. Overall design: This study contains the following five indepdent experimental setups, also denoted as experimental batches: 1. RNAseq of whole hippocampal lysate of aged mice continuously infused for 6 days with young mouse CSF or artificial CSF as control (aCSF n=8, YM-CSF n=7). 2. To gain a deeper mechanistic understanding of the cellular processes induced by young CSF in OPCs we metabolically labeled nascent mRNA with 4-thiouridine (s4U) using thiol(SH)-linked alkylation and sequenced RNA (SLAMseq) from cultured OPCs 1- or 6 hr after exposure to YH-CSF (a total of 4 groups; 1hr aCSF n=4, rest n=5). 3. Sorted OPC (olig2_high) and OL (olig2_low) nuclei from 4 young and 4 aged hippocampi (aged OL n=3, rest n=4). 4. Sorted OPC (olig2_high) nuclei from hippocampi of aged mice 1hr or 6hr following acute interacerebroventricular injection of aCSF or young mouse CSF (total of 4 groups, n=4 each). 5. Sorted OPC (olig2_high) nuclei from hippocampi of aged mice 16hr following acute interacerebroventricular injection of aCSF, young mouse CSF or aged mouse CSF (total of 3 groups, aCSF n=3, rest n=4 mice each).