番茄社区

Transfusing cerebrospinal fluid (CSF) from young mice to old ones boosted the memory of the older animals, a groundbreaking study showed.

The CSF infusion triggered fibroblast growth factor (FGF) signaling pathways, which activated a transcription factor called SRF that promoted pathways leading to the proliferation and maturation of oligodendrocytes, reported Tony Wyss-Coray, PhD, of Stanford University School of Medicine in California, and colleagues in . The oligodendrocytes produced myelin to support neuronal signaling, which led to improved memory.

"The broad message here is that the aging process is malleable, which of course is not new because of this paper," Wyss-Coray said in an interview with 番茄社区. "But it adds to the idea that aging is a potential therapeutic target, a process we can start to understand better and start to manipulate."

"The other message -- one that's more brain-specific -- is that if you improve the environment in which neurons live, you can actually have a substantial improvement in function," he added. "That may be as important, or even more important sometimes, than targeting neuronal processes themselves."

CSF is the clear liquid that bathes the brain, "the environment in which the brain swims, if you will," Wyss-Coray noted. "It's part of the immediate environment of the brain, but we know very little about what its components do."

Over 7 days, Wyss-Coray and colleagues infused CSF from young adult mice that were 10 weeks old into the brains of older adult mice that were 18 months old. The treatment improved the memory recall of the older animals in a fear-conditioning task in which they learned to associate a small foot shock with a tone and flashing light.

The researchers "have broken ground in the field of brain health and aging by discovering that young CSF contains a factor that aids memory recall in older mice through oligodendrocyte maturation and myelination in the hippocampus," noted Maria Lehtinen, PhD, and Miriam Zawadzki, MD/PhD candidate, both of Boston Children's Hospital, in an accompanying .

Earlier work showed that fear-conditioning in mice required oligodendrocyte proliferation and myelin formation and that disrupting this process impaired memory, they observed. This raised the question of whether young CSF might affect the proliferation and maturation of oligodendrocyte precursor cells (OPCs).

"Indeed, [the researchers] found that young CSF more than doubled the percentage of OPCs actively proliferating in the hippocampus of old animals," Lehtinen and Zawadzki wrote. "This cellular change was followed 3 weeks later by an increase in myelin production. The findings strongly suggest that young CSF improves the cognitive abilities of aged mice by modulating oligodendrocytes."

When Wyss-Coray and colleagues studied primary OPC cultures, they saw the greatest increase in gene expression in response to young CSF treatment was in serum response factor (Srf), which encodes a transcription factor that initiates cell proliferation and differentiation.

When they screened for potential SRF activators in CSF, they found that fibroblast growth factor 17 (Fgf17) infusion was sufficient to induce OPC proliferation and long-term memory consolidation in aged mice, and that blocking Fgf17 impaired cognition in young mice.

"This suggests that Fgf17 is not only able to recapitulate some of the useful effects of CSF from young mice, but it also seems to be necessary to make a young brain function at its full capacity," Wyss-Coray said.

The study was inspired by Wyss-Coray's past work that showed blood from young mice could restore memory function in older animals. Looking at brain aging holistically may provide an opportunity to tackle intractable diseases of aging like Alzheimer's, he pointed out.

"Our standard approach in medicine has been to identify the pathology, to diagnose and monitor the pathology, and to try to intervene with the pathology," Wyss-Coray said. "But another approach may be to try to restore overall body and tissue function and use that to figure out what key ingredients are responsible for improvements."

"One step that we haven't really proven is whether you can reduce this to one factor, or to a few factors, that you could turn into a medicine," he acknowledged. "It might just be that you need nature's cocktail to get the effect, and you can't really dissect it too much."

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