Age-related cognitive decline should be a concern to all of us(!!). Whereas a healthy diet and regular exercise can help slow down or prevent this decline, as yet there are no treatments to reverse gradual diminution in memory. As a possible means of treatment, authors [see attached article & editorial] focused on cerebrospinal fluid (CSF) — which bathes brain tissue and contains several protein growth-factors necessary for normal brain development.
CSF from young adult mice (10 weeks old) was infused into the brains of aged mice (18 months old) over 7 days. This treatment improved memory recall of the old animals in a fear-conditioning test (in which they learn to associate a small electric shock with a tone and flashing light). Authors then sought to determine how CSF treatment might alter gene expression in the hippocampus (a key memory center in the brain that’s often the focus of studies of age-associated cognitive decline). Cells in the central nervous system (CNS) called oligodendrocytes produce myelin (a fatty protein-rich material that insulates neuronal fibers called axons). Myelination of axonal projections throughout the brain ensures that strong signal connections between neurons are maintained.
Authors found that genes typically expressed in oligodendrocytes were highly up-regulated in old mice treated with CSF from young mice (compared with that in control animals treated with artificial CSF). Previous work had demonstrated that successful
fear-conditioning in mice requires oligodendrocyte proliferation and myelin formation, and that disruption of this process impairs memory. Authors therefore found that “young CSF” more than doubled the number of oligodendrocyte precursor cells (OPCs) in the hippocampus of old animals; this cellular change was followed 3 weeks later by an increase in myelin production. Their findings strongly suggest that young CSF improves the cognitive abilities of aged mice by modulating oligodendrocyte proliferation and maturation.
The greatest increase in gene expression in response to young CSF treatment was in the serum response factor gene (Srf), which encodes a transcription factor that initiates cell proliferation and differentiation. Six hours after young human CSF administration to OPC cultures, Srf expression had returned to baseline levels, but downstream targets — related to cell cycle and proliferation — were up-regulated. The authors confirmed that these SRF-signaling pathways were also activated in old mice after young CSF
CSF contains a rich cocktail of signaling molecules and growth factors — many of which could induce the SRF-signaling pathways seen in OPCs. Authors searched for candidate factors capable of inducing Srf expression in published protein databases, and fibroblast growth factor-17 (FGF17) emerged as the most compelling candidate. They then showed that FGF17 is robustly expressed in mouse neurons, exhibits decreased expression in aged mice, and induces OPC proliferation in rat cultured OPCs.
FGF17 infusion into old CSF partially recapitulated the effects of the young CSF, both in cell culture and in the intact animal, improving memory recall of aged mice. Finally, authors demonstrated that inhibition of FGF17 in cultured OPCs treated with young CSF was sufficient to inhibit OPC proliferation, and that treatment of young mice with FGF17 blockers impaired cognition. These data strongly suggest that FGF17 is a CSF-borne factor crucial for cognition, and show that its effects are probably mediated by oligodendrocytes and myelination in the hippocampus. How FGF17 is distributed in the CSF and delivered to target cells in the hippocampus presents a new direction of research. 😊
Probably several start-up companies have already begun to synthesize FGF17, and to write up clinical research proposals to treat patients in memory-care centers — and to help politicians whose brains always seem to be failing. 😉
Nature 19 May 2022; 605: 509-515 & News-N-Views pp 429-429