Young CSF restores oligodendrogenesis and memory in aged mice via Fgf17

Tal Iram (), Fabian Kern, Achint Kaur, Saket Myneni, Allison R. Morningstar, Heather Shin, Miguel A. Garcia, Lakshmi Yerra, Robert Palovics, Andrew C. Yang, Oliver Hahn, Nannan Lu, Steven R. Shuken, Michael S. Haney, Benoit Lehallier, Manasi Iyer, Jian Luo, Henrik Zetterberg, Andreas Keller, J. Bradley Zuchero and Tony Wyss-Coray ()
Additional contact information
Tal Iram: Stanford University School of Medicine
Fabian Kern: Stanford University School of Medicine
Achint Kaur: Stanford University School of Medicine
Saket Myneni: Stanford University School of Medicine
Allison R. Morningstar: Stanford University School of Medicine
Heather Shin: Stanford University School of Medicine
Miguel A. Garcia: Stanford University School of Medicine
Lakshmi Yerra: Palo Alto Veterans Institute for Research
Robert Palovics: Stanford University School of Medicine
Andrew C. Yang: Stanford University School of Medicine
Oliver Hahn: Stanford University School of Medicine
Nannan Lu: Stanford University School of Medicine
Steven R. Shuken: Stanford University School of Medicine
Michael S. Haney: Stanford University School of Medicine
Benoit Lehallier: Stanford University School of Medicine
Manasi Iyer: Stanford University School of Medicine
Jian Luo: Stanford University School of Medicine
Henrik Zetterberg: Sahlgrenska Academy at the University of Gothenburg
Andreas Keller: Stanford University School of Medicine
J. Bradley Zuchero: Stanford University School of Medicine
Tony Wyss-Coray: Stanford University School of Medicine

Nature, 2022, vol. 605, issue 7910, 509-515

Abstract: Abstract Recent understanding of how the systemic environment shapes the brain throughout life has led to numerous intervention strategies to slow brain ageing1–3. Cerebrospinal fluid (CSF) makes up the immediate environment of brain cells, providing them with nourishing compounds4,5. 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.

Date: 2022
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DOI: 10.1038/s41586-022-04722-0

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