Although a healthy diet and optimal exercise can slow the progression of aging associated cognitive decline, neurodegenerative disease and dementia, there are currently no therapies to reverse these pathologies.
In a study conducted on mice, published in the journal Nature on May 11, 2022, “Young CSF restores oligodendrogenesis and memory in aged mice via Fgf17” scientists demonstrate, infusing old mice with cerebrospinal fluid (CSF) from young mice promotes the production of the fatty sheath of myelin that surrounds the extended axonal shafts of neurons. This enhanced myelin formation, that is attributed to growth factors in the CSF, in turn restores neuron function and memory recall in the aged animals.
The findings provide insights on systemic factors in the CSF that affect neuronal functions, thereby suggesting potential rejuvenating therapies for the aging brain.
CSF is a clear protective liquid that surrounds the brain and spinal cord in all vertebrates and provides neurons in the brain with nutrients, molecular messages and growth promoting factors. The mechanisms through which CSF slows brain aging are however not clear.
A team led by Tony Wyss-Coray, PhD, a professor of neurology at Stanford University, used transcriptomics, cell proliferation and survival assays, and a battery of behavioral paradigms to test the rejuvenating properties of 10-week-old CSF when injected into 18-month-old mice. They found the infusion improves memory function in older animals and investigated the cellular and molecular mediators the resulted in this outcome.
Through an unbiased transcriptome analysis of the hippocampus—a horn shaped structure in each hemisphere of the brain that consolidates short-term and spatial memory—the researchers found specialized cells called oligodendrocytes to be most responsive to youthful CSF.
Oligodendrocytes, also called oligodendroglial cells are, a type of supportive neuroglial cell that, among other functions, insulates axons in the brain and spinal cord by wrapping around axonal shafts, forming of myelin sheaths.
Conducting in vivo experiments in rejuvenated older mice and in vitro experiments on primary cultures of progenitor cells that form oligodendrocytes (OPCs), the researchers showed CSF from young mice increases cell division and maturation in oligodendrocytes of the hippocampus.
The investigators then employed an RNA sequencing protocol called SLAMseq that measures newborn RNAs over time in response to a stimulus. Using this method, the researchers found that in response to young CSF, a transcription factor called SRF (serum response factor) that drives the rearrangement of a cell’s actin cytoskeleton, mediates the rapid division of OPCs. They also showed that in aged mice, the expression of SRF in hippocampal OPCs decreases.
Taking the quest a step further, the scientists searched for factors that activate SRF in the CSF, and found a growth factor called Fgf17 (fibroblast growth factor 17). They then infused aged mice with Fgf17 instead of young CSF and found this to be sufficient in coaxing hippocampal OPCs to multiply and improve memory recall. To further support their hypothesis that Fgf17 improves cognition in older mice, they blocked Fgf17 in young mice, and found this impaired their memory recall.
In a news and views article on the study, Maria Lehtinen, PhD, an associate professor at the Boston Children’s Hospital and her mentee, Miriam Zawadzki, PhD, note, “Not only does the study imply that FGF17 has potential as a therapeutic target, but it also suggests that routes of drug administration that allow therapeutics to directly access the CSF could be beneficial in treating dementia.”
