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CSF From Young Mice Restores Memory in Aged Mice

Infusing cerebrospinal fluid (CSF) from young mice into the brains of their aged counterparts improves their memory functioning and the myelination of the hippocampus, a May 11 paper in Nature found.

An international team of neuroscientists identified oligodendrocytes in the hippocampus to be the chief beneficiary of the treatment. The young CSF boosted the proliferation and differentiation of oligodendrocyte progenitor cells (OPC).

Going further, they identified a transcription factor called serum response factor (SRF) as a key mediator of the effects of young CSF. Although SRF expression decreases with age, they found acute injection of young CSF increased it.

The group then screened for potential activators of SRF in CSF. They observed that infusion with fibroblast growth factor 17 (Fgf17) was sufficient to induce the benefits that occurred young CSF, including proliferation of SRF and restoration of long-term memory consolidation in aged mice. Blocking Fgf17, on the other hand, impaired 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," wrote senior study author Tony Wyss-Coray, PhD, professor of neurology and neurological sciences at Stanford University, and colleagues.

Dr. Wyss-Coray has spent nearly a decade studying the restorative effects of serum from young or exercising mice. In December, his group published a paper in Nature showing that serum from exercising mice improved memory in sedentary mice. That paper also identified a protein, clusterin, that mediated most of the benefits.

As previously reported in Neurology Today, recent papers have identified other potential factors mediating the neurocognitive benefits of exercise and youth. In August of 2020, a paper in Nature Metabolism identified the hormone irisin as conferring the neurocognitive benefits of exercise. A year earlier, a paper in Science identified the liver enzyme GPLD1 as playing a key role. Yet another hormone that appears to transduce the cognitive benefits of exercise, klotho, was first discovered in 1997.

Dr. Wyss-Coray's group turned to CSF in the current study, rather than blood plasma, because they suspected that the blood-brain barrier could impede the rejuvenation potential of clusterin or other factors found in the blood.

To test the effects of CSF from young mice on older ones, Dr. Wyss-Coray's group studied 20-month-old mice who received three foot shocks associated with a tone and a flashing light. The mice were then split into two groups and infused with either artificial CSF or CSF from the young mice for one week. They tested memory recall three weeks later; the animals that had received young CSF displayed a higher average freezing rate following exposure to the tone and light, demonstrating improved fear memory.

The researchers then measured the effect of young CSF on the hippocampal transcriptome. After initially identifying 271 differentially expressed genes, they found that transcription of oligodendrocyte genes was highly upregulated, Young CSF, they also reported, “induced a 2.35-fold increase in the percentage of proliferating the CA1 region of the hippocampus but not in the cortex."

To gain a better understanding of which factor in young serum was driving the effects on aged mice, they labeled new mRNA being generated after transfusion, and found that the gene most strongly induced one hour after treatment was SRF. They then determined that Fgf17 is a key metabolic inducer of SRF. Infusing Fgf17 into the CSF of aged mice partially reproduced the neurocognitive effects of young CSF, while blocking it impaired memory. 

The paper concluded: “Combined, our results suggest that targeting hippocampal myelination through factors present in young CSF might be a therapeutic strategy to prevent or rescue cognitive decline associated with ageing and neurodegenerative diseases."

Dr. Wyss-Coray and first author Tal Iram, PhD, are co-inventors on a patent application related to the work published in this paper. See the paper for disclosures of coauthors.

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