A team at Stanford University has demonstrated a new approach to reversing memory loss in mice.
An infusion of spinal fluid from young mice reversed the memory loss commonly seen in aged animals, the team reported this month in the journal Nature.
A growth factor found in the fluid also improved memory, albeit to a lesser degree, says Tony Wyss-Coray, a neuroscientist and lead author of the study.
“When we put the factor in mice, they’re actually more able to perform a memory task where they have to remember something that happened to them (a small electric shock),” says Wyss-Coray.
The finding points to “a new era” in the search for treatments for Alzheimer’s disease and other age-related conditions that affect a person’s memory and thinking, says Maria Lehtinen, a neuroscientist at Harvard Medical School, who wrote a commentary accompanying the study.
To date, most efforts to treat Alzheimer’s have focused on removing the hallmarks of the disease – toxic plaques and messes that build up in the brain. These efforts have produced drugs that can reduce plaque and tangles, but they still have a long way to go to preserve a person’s thinking and memory.
Recent results with cerebrospinal fluid suggest that other treatments may help, even if they do not affect the underlying disease process.
“What we’re seeing is that there’s a lot more and that aging seems to produce a lot of abnormalities that contribute to cognitive decline and dementia,” says Wyss-Coray.
A balm for forgotten mice
The new study involved large mice, which, like their human counterparts, tend to develop memory problems.
For example, a painful experience will form a memory that lasts for weeks or even months in a young animal, says Wyss-Coray. As a result, the animals will continue to freeze in response to a light or sound signal that was previously accompanied by an electric shock.
“When they grow up, they don’t forget to forget about it,” he says. “After a few days they don’t remember that they were in a bad mood.”
Wyss-Coray’s lab wondered if one of the causes of his fading memory could involve cerebrospinal fluid or CSF, which bathes the brain and spinal cord. Brain cells depend on this fluid and its composition changes drastically as an animal ages.
But they had not tried the idea because extracting spinal fluid from a small animal is very difficult. That changed, thanks to Tal Iram, a postdoctoral researcher in the lab who was determined to overcome technical hurdles.
In a meticulous process that took many months, Iram was able to collect enough liquid cenyi from the young mice to conduct an experiment that infused the liquid into large animals.
“We hoped that by mimicking a young environment, the brain would respond to this with better function,” says Wyss-Coray.
It worked.
Old mice began to do as well as their younger counterparts when it came to remembering an experience. It was a remarkable result, but the team still needed to find out why the experiment worked.
Thus, they performed genetic tests that showed that the greatest response to young spinal fluid was found in some specialized cells in the hippocampus, an important area for memory.
These cells, called oligodendrocytes, create the myelin sheath that insulates the wiring in the brain and is also important for memory.
Further evidence suggested that oligodendrocytes responded to a spinal fluid growth factor called FGF17, which decreases with age.
The team’s success in improving memory with FGF17 is important because it could lead to a drug that could be mass-produced. But even if this drug were to arrive, scientists would have to figure out how to deliver it safely to the human brain.
More factors to come
FGF17 is probably just one of many substances involved in brain aging, says Wyss-Coray. But its effectiveness in mice suggests that restoring just one of these substances may make a difference.
An aging brain with memory loss is a bit like “an old car that has broken down,” he says. “But just like repairing a car, you don’t necessarily have to fix all the parts, you have to find the key parts.”
At least some of these parts are likely to be in the spinal fluid, Lehtinen says.
His own laboratory has been studying the role of cerebrospinal fluid in the development of the mouse brain.
“We’ve found that CSF provides these important health and growth-promoting factors that can essentially modulate brain growth,” he says. “What is missing so far is the next step in testing whether these CSF factors can benefit adults [brains]. ”
The new study suggests they can, he says.
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