For a human, one of the first signs someone is getting old is the inability to remember little things; maybe they misplace their keys, or get lost on an oft-taken route. For a laboratory mouse, it’s forgetting that when bright lights and a high-pitched buzz flood your cage, an electric zap to the foot quickly follows.
But researchers at Stanford University discovered that if you transfuse cerebrospinal fluid from a young mouse into an old one, it will recover its former powers of recall and freeze in anticipation. They also identified a protein in that cerebrospinal fluid, or CSF, that penetrates into the hippocampus, where it drives improvements in memory.
The tantalizing breakthrough, published Wednesday in Nature, suggests that youthful factors circulating in the CSF, or drugs that target the same pathways, might be tapped to slow the cognitive declines of old age. Perhaps even more importantly, it shows for the first time the potential of CSF as a vehicle to get therapeutics for neurological diseases into the hard-to-reach fissures of the human brain.
“This is the first study that demonstrates real improvement in cognitive function with CSF infusion, and so that’s what makes it a real milestone,” said Maria Lehtinen, a neurologist at Boston Children’s Hospital and Harvard Medical School, who was not involved in the new research. “The super-exciting direction here is that it lends support to the idea that we can harness the CSF as a therapeutic avenue for a broad range of conditions.”
CSF is a clear liquid that flows in around the hollow cavities of the brain and spinal cord, bathing them in nutrients and clearing away cellular waste. It’s produced in a tissue called the choroid plexus, which in an adult human pumps out between 400 and 600 milliliters of the stuff each day (roughly 2 cups). As it circulates, CSF picks up anything that the cells it passes are secreting, so for decades scientists and doctors have monitored it for signs of disease-indicating distress, like beta-amyloid in the case of Alzheimer’s.
Only in the last 10 years have researchers begun to probe whether the CSF is more than just a passive chemical current and in fact has an active role to play in directing development and maintaining brain health. It’s a hypothesis that’s been hard to test because of the difficulties of reaching into the sealed-off channels where CSF circulates. It’s so challenging, that when Stanford University neurologist Tony Wyss-Coray was approached by postdoc Tal Iram about transfusing CFS from young mice into old mice, he tried everything to talk her out of it.
Since the late 1990s, Wyss-Coray has been studying the aging brain, trying to map all the ways it can sputter out as we get old and chart possible course corrections. The obvious place to start was the CSF, he told STAT, because it represented the direct environment where cells of the brain reside. But it was just too technically daunting. So in the mid-2000s, he turned to studying the next best thing: blood. In 2014, his lab showed that an influx of young blood improved memory and learning in middle-aged mice using a technique that involved stitching young mice to old ones, and fusing their blood vessels to create a two-animal circuit.
But there’s no way to do that with brains. So Iram instead embarked on a series of high-stakes surgeries, where any errant nick of the scalpel could send blood into the CSF, polluting it with proteins and rendering the sample unusable. First, she painstakingly extracted CSF from anesthetized young mice, drawing out all she could from their pea-sized brains — about 10 microliters, or one-tenth the volume of a single drop of blood. When she had collected about 90 microliters, she put the young CSF in a container implanted into the back of an old mouse, which slowly pumped the liquid through a tiny tube into the animals’ brain over the course of seven days.
A week and a half later, when these mice were exposed to the same stimulus they’d been trained on pre-infusion (the flashing light and the buzzing tone), they froze more often than mice of the same age and training who hadn’t received young CSF. They were better able to recall the fear memory associated with the electric shock.
Next, Iram and her colleagues used single-cell RNA sequencing to pry open the memory centers of these mice, the hippocampus, where they found about 270 genes whose expression had changed in response to the young CSF. They saw the biggest changes in a specific type of cell called oligodendrocytes, which produce myelin — a fat and protein-rich material that coats the connections between neurons.
“These are the cells that basically make the insulation over the wiring between nerve cells in the brain — it’s like the plastic cover over a cable,” said Wyss-Coray. “They’re crucial to allowing the nerve cells to communicate effectively with each other. And we found that in response to the young CSF, there are more of these cells being produced, and they’re better insulators.”
Recent studies have shown that as you make new memories and neurons lay in new connections, they send signals to a population of stem cells, instructing them to morph into new oligodendrocytes. But as people get older, those signals start to peter out, resulting in fewer oligodendrocytes, less myelin, and weaker communication between neurons — the biological precursor to memory loss.
Wyss-Coray’s team sifted through these signals and found a promising candidate, a fibroblast growth factor called Fgf17, which triggers oligodendrocyte proliferation in young mice and decreases expression as they get older. When they infused just Fgf17 into the CSF of aged mice, they saw similar memory improvements as with the young CSF. Finally, they infused young mice with an anti-Fgf17 antibody to block their cells from taking it up, which impaired their recall and decreased their performance in a maze challenge.
“This lends additional support to this concept of changing the environment to change brain function,” Wyss-Coray said. “The principle fluid that the brain swims in contains a lot of exciting information, not just about factors entering the spinal fluid as a consequence of aging or disease, but it’s an active fluid that can actually rejuvenate the brain. So it’s a source of entirely new biology that people have only just begun to pursue.”
But don’t expect to see young CSF infusion services popping up any time soon. A more likely translational approach will be to try to mimic the effects of Fgf17 with a small-molecule drug, said Wyss-Coray, something that will require much more research in the years ahead.
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