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Rejuvenation of the brain by FGF17 and more myelin sheaths ?


It has long been a wish of many people to reverse the effect of aging by a fountain of youth. Indeed, there are experimental approaches that improve cognitive functions in aging brains through systemic interventions, for example by transferring blood plasma from young to old organisms. However, it is still unclear what factors might be responsible for this effect.


As explained in my book on Neurodegeneration, the metalloproteases released by inflammatory cells have been studied most in this context so far. These are zinc- and calcium-dependent endopeptidases that cleave extracellular matrix molecules (laminin, collagen, fibronectin, and others). A natural inhibitor of these proteases, TIMP-2 (tissue inhibitor of metalloproteinases 2), was found to be responsible for the rejuvenation effect after blood plasma transfusion. In the experiments by Tony Wyss-Coray's research group published in 2017, the memory of old mice improved when they were injected with the blood plasma of young people. The authors hypothesized that metalloproteases released from activated microglial cells were involved in aging processes by loosening synaptic contacts that should be permanently stabilized by extracellular matrix proteins.


In a new study, the same group has now demonstrated that infusions of young cerebrospinal fluid (CSF) into the brains of old mice promote the formation of a specific type of glia (oligodendrocytes) and improve memory functions. Since oligodendrocytes form the myelin in the CNS (see image below), it is thus suspected that improved myelination may restore cognitive functions in old age. A fibroblast growth factor (FGF17) appears to play a key role in this process.


On the right of the image is a myelin sheath (blue), which is formed by oligodendrocytes and serves as an electrical insulator (the axon is shown in red). On the left of the image is an 'opened' neuron with several processes and a schematic representation of the most important intracellular organelles.


The authors of the new paper found that administration of young mouse CSF (over a week) or a direct injection of FGF17 had a positive effect on the memory of old mice. This was particularly evident in the so-called conditional fear response in which the "freezing" of the animals is observed after weak electric shocks combined with sound or light stimuli. This conditioned response was more likely to be elicited in older animals treated with young mouse CSF than in untreated older controls; thus, the animals had better memory of fearful experiences.


Subsequently, RNA sequencing revealed upregulation of transcription factors involved in oligodendrocyte differentiation and in the production of myelin components. The authors demonstrated that young CSF increased the proportion of proliferating oligodendrocyte progenitor cells (OPCs) in the hippocampus of old mice. Interestingly, these cells showed a strong induction of serum response factor (SRF).


Searching for molecules that induce SRF in CSF, the authors identified FGF17 as the molecule that increases the proliferation of OPCs in old mice and improves memory performance in anxiety tests, suggesting that FGF17 treatment can simulate the effect of infusing young CSF into old mice. FGF17, whose levels in mice and human CSF decrease with age, is thus necessary and sufficient to improve cognition in aged animals. Conversely, blocking FGF17 by infusion of an inhibitory antibody leads to impaired memory functions in mice.


It has long been known that FGF17 is critical for embryonic brain development, but we knew little about its function in the adult nervous system. Young mice lacking FGF17 have smaller brains and show abnormalities in social behavior. The new results underscore that close examination of cerebrospinal fluid can greatly expand our understanding of aging processes in the brain and reveal new therapeutic strategies to treat neurodegeneration.


References:


Iram T, Kern F, Kaur A, Myneni S, ... , Keller A, Zuchero JB, Wyss-Coray T. (2022) Young CSF restores oligodendrogenesis and memory in aged mice via Fgf17. Nature 605:509


Yates D. (2022) Restoring the aged brain with CSF. Nature Reviews Neuroscience 23:393


Image credit: iStock/fizkes and iStock/Christoph Burgstedt

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