As the human population ages and the cost of neurodegenerative age-related diseases balloons, scientists focus increased efforts on studying the biological pathways involved in aging and how they contribute to cognitive decline (1). In a recent study, researchers have taken a step toward elucidating this process by studying the role of age-related changes in the composition of cerebrospinal fluid in memory decline.
Cerebrospinal fluid (CSF) is a protein-rich solution bathing the brain’s ventricles and spinal cord that supports the nervous system. As the brain ages, the level of inflammatory factors in the CSF increases, and that of growth factors decreases. To find out if these changes affect brain function, a team of scientists at Stanford University investigated whether infusing CSF from young mice into old mice would rejuvenate their aged brains (2).
“We know even in humans that CSF proteins change dramatically with age, but we don't know what's the function of that. How does that affect function, either in the cells or in the brain?” asked Tal Iram, a neuroscientist at Stanford University School of Medicine and coauthor of the study. “We're still deep diving into those mechanisms.”
Iram and her team carefully injected young CSF into the ventricles of old mice’s brains and evaluated the old mice for behavioral changes. Old mice infused with young CSF better responded to a learning stimulus, which led the researchers to look at their hippocampi, the brain’s memory center. The team used RNA sequencing to study how the young CSF may have changed hippocampal gene expression to improve memory. They observed upregulated expression of a particular transcription factor known as serum response factor (SRF) that supports the growth and differentiation of oligodendrocytes, central nervous system cells linked to memory function (3).
In further analyzing the young CSF, the scientists pinpointed a growth factor known as fibroblast growth factor 17 (FGF17) that activates SRF and supports oligodendrocyte proliferation. The researchers injected FGF17 into the ventricles of old mice and found that the mice showed memory improvements comparable to the effect achieved with the young CSF. The researchers then administered an FGF17-blocking antibody to the young mice and observed that inhibiting FGF17 impaired neural plasticity and oligodendrocyte proliferation. As FGF17 is known to decrease in the human CSF with age, these results suggest a role for this growth factor in memory function.
Iram and her team are interested in understanding how the CSF composition’s influence on memory could inform new therapies. They are particularly interested in exploring whether upregulating the expression of SRF-activating growth factors using drugs might help prevent age-related memory decline.
“In terms of the impact of this work, it does move the CSF story really more securely into the space of potential therapeutics for the downside of the trajectory of brain health,” said Anthony-Samuel LaMantia, a neuroscientist at Virginia Tech who was not affiliated with the study.
LaMantia pointed out that the data were collected one week after the CSF infusions, making it challenging to determine whether these CSF-induced changes were transient or long term.
References
- Alzheimer’s Association. 2023 Alzheimer’s Disease Facts and Figures. At <https://www.alz.org/media/documents/alzheimers-facts-and-figures.pdf>.
- Iram, T., Kern, F., Kaur, A. et al. Young CSF restores oligodendrogenesis and memory in aged mice via Fgf17. Nature 605, 509–515 (2022).
- Munyeshyaka, M., Fields, R.D. Oligodendroglia are emerging players in several forms of learning and memory. Commun Biol 5, 1148 (2022).
