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Young brain fluid improves memory in old mice

ice sit in a container at a Cyagen Biosciences Inc. facility in Taicang, Jiangsu province, China.

Young cerebrospinal fluid probably improves the conductivity of the neurons in ageing mice.Credit: Qilai Shen/Bloomberg/Getty

Scientists have been trying to unravel the mysteries of why memory diminishes with age for decades. Now they have discovered a possible remedy — cerebrospinal fluid from younger brains1.

Cerebrospinal fluid (CSF) from young mice can improve memory function in older mice, researchers report today in Nature. A direct brain infusion of young CSF probably improves the conductivity of the neurons in ageing mice, which improves the process of making and recalling memories. The team also suggests that the improvements are largely due to a specific protein in the fluid.

“This is super exciting from the perspective of basic science, but also looking towards therapeutic applications,” says Maria Lehtinen, a neurobiologist at Boston Children’s Hospital in Massachusetts.

CSF is the central nervous system’s version of plasma: a soup of essential ions and nutrients that cushions the brain and spinal cord and is essential for normal brain development. Physicians frequently use it as an indicator of brain health, and a biomarker of neurological diseases. But as mammals age, CSF loses some of its punch. Those changes might affect cells related to memory, says co-author Tal Iram, a neuroscientist at Stanford University in California. “Could we do something about it by re-exposing these cells to younger CSF?” she asks. “That was the overarching question.”

Testing memory

The first step for Iram and her team was to give ageing mice an experience they would remember. The team gave 20-month-old mice three small electric shocks on their foot in tandem with several flashes of light and sound, to create an association between the lights and the shock. The researchers then infused the brains of one group of 8 mice with CSF from 10-week-old mice, while a control group of 10 mice were given artificial CSF.

After three weeks the mice faced the same sounds and lights, but this time without a shock — recreating the context of the fear without the actual fear-inducing action. Mice that receive young CSF remembered the shock and froze in fear almost 40% of the time, but that happened only around 18% of the time in mice given artificial CSF. The findings suggest that young CSF can restore some declines in ageing-brain abilities. “The broader implication is that the brain is still malleable and there are ways to improve its function,” says co-author Tony Wyss-Coray, a neuroscientist at Stanford. “It’s not all lost.”

The work on CSF is inspired by Wyss-Coray’s past work showing that plasma from young mice could restore memory function in older rodents2,3. A start-up co-founded by Wyss-Coray, Alkahest in San Carlos, California, has conducted small trials suggesting some cognitive benefits in mice and people with dementia given the company’s plasma-derived products. Other groups are exploring different methods for using young plasma, but the field is still in its infancy.

The brain’s wiring

The hippocampus is the brain’s memory control centre: it is responsible for creating, retaining and recalling memories. The team therefore looked at this seahorse-shaped structure to get a better understanding of how young CSF might improve the memory function of ageing mice. The researchers found that the structure upregulated genes related to a cell called an oligodendrocyte. Oligodendrocytes produce the myelin sheath around neurons’ tails, essentially “the plastic coating over the wires in the brain”, says Wyss-Coray. And like wire insulation, that sheathing helps with conductivity. Specifically, the CSF helps to generate more of the early-stage oligodendrocytes known as oligodendrocyte progenitor cells. Generating more cells that insulate nerve connections helps to maintain brain function, Wyss-Coray adds.

The researchers also isolated a protein from the CSF cocktail that another analysis had suggested was a compelling candidate for improving memory: fibroblast growth factor 17 (Fgf17). Infusion of Fgf17 had a similar memory-restoring effect to infusing CSF. Furthermore, giving the mice an antibody that blocked Fgf17’s function impaired the rodents’ memory ability. Wyss-Coray and Iram have applied for a patent on their findings around Fgf17.

Tricky techniques

It took more than a year for Iram to perfect the process of collecting CSF and infusing it into another brain. Collection is extremely challenging, she says, and has to be done with precision. Any blood contamination will ruin the fluid. Pressure in the brain is a delicate balance, so infusion must be slow and in a specific location within the brain: the cerebral ventricle. The delicate procedure might pose challenges for use in people, says Julie Andersen, who studies Alzheimer’s and Parkinson’s disease at the Buck Institute for Research on Aging in Novato, California.

“These are really labour-intensive and extremely challenging experiments. They've done a lot of really beautiful work here,” adds Lehtinen, who wrote an accompanying News & Views article in Nature4.

Fgf17 and CSF seem to be promising elixirs for brain health, but investigating the ways in which CSF interacts with oligodendrocytes, and how those cells are involved in memory, will be important to improving our understanding of brain ageing, say Iram and Wyss-Coray. There are probably other factors in the CSF besides Fgf17 that influence cognitive function, say Andersen and Lehtinen.

Although extracting CSF from the body is challenging, Lehtinen notes that there is no shortage of the fluid in the patient population. “We can really start envisioning different ways of developing new treatments and therapies.”

doi: https://doi.org/10.1038/d41586-022-01282-1

Updates & Corrections

  • Update 12 May 2022: This story has been updated to include details of Tony Wyss-Coray and Tal Iram's patent application.

  • Correction 13 May 2022: A previous version of this story misstated the results of the trial in mice.

References

  1. Iram, T. et al. Nature 605, 509–515 (2022).

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  2. Villeda, S. et al. Nature Med. 20, 659–663 (2014).

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  3. Castellano, J. et al. Nature 544, 488–492 (2017).

    PubMed  Article  Google Scholar 

  4. Zawadzki, M. & Lehtinen, M. K. Nature https://doi.org/10.1038/d41586-022-00860-7 (2022).

    Article  Google Scholar 

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