A substance found in young spinal fluid helps old mice remember

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 typically seen in aging animals, the team reported this month in the journal Nature.

A growth factor found in the fluid also improved memory, though to a lesser degree, says Tony Wyss-Coray, a neuroscientist and senior author of the study.

"When we put the factor in the mice, they actually are better able to perform a memory task where they have to remember something that happened to them (a small electric shock)," Wyss-Coray says.

The finding hints at "a whole 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 that accompanied the study.

So far, most efforts to treat Alzheimer's have focused on eliminating the disease's hallmarks: toxic plaques and tangles that build up in the brain. Those efforts have produced drugs that can reduce the plaques and tangles, but have yet to do much to preserve a person's thinking and memory.

The latest results with spinal fluid suggest other treatments can help, even if they don't affect the underlying disease process.

"What we're seeing is that there's much more going on and that aging seems to produce a lot of abnormalities that contribute to cognitive decline and dementia," Wyss-Coray says.

A Balm for Forgetful Mice

The new study involved elderly mice, who, 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, Wyss-Coray says. As a result, the animals will continue to freeze in response to a light or sound cue that was once accompanied by an electric shock.

"When they're old, they keep forgetting about this," he says. "A few days later they can't remember that they were in a bad environment."

Wyss-Coray's lab wondered whether one cause of their fading memory might involve cerebrospinal fluid, or CSF, which bathes the brain and spinal cord. Brain cells depend on this fluid, and its composition changes dramatically as an animal gets older.

But they hadn't tested the idea because extracting spinal fluid from a tiny animal is so difficult. That changed, thanks to Tal Iram, a postdoctoral research fellow in the lab who was determined to overcome the technical obstacles.

In a painstaking process that took many months, Iram was able to collect enough spinal fluid from young mice to conduct an experiment that infused the liquid into older animals.

"We were hoping that by mimicking a young environment, that the brain would respond to that with better function," Wyss-Coray says.

It worked.

The old mice began to do about as well as their younger counterparts when it came to recalling an experience. That was a remarkable result, but the team still needed to figure out why the experiment worked.

So they conducted genetic tests that showed the greatest response to the young spinal fluid was found in some specialized cells in the hippocampus, an area that's important to memory.

These cells, called oligodendrocytes, create the myelin sheath that insulates wiring in the brain and is also important to memory.

More tests suggested that the oligodendrocytes were responding to a growth factor in spinal fluid called FGF17, which dwindles with age.

The team's success improving memory with FGF17 is important because it could lead to a drug that could be mass produced. But, even if such a drug arrived, scientists would have to figure out how to safely deliver it to a human brain.

More factors to come

FGF17 is probably just one of many substances involved in brain aging, Wyss-Coray says. But its effectiveness in mice suggests that restoring just one of these substances can make a difference.

An aging brain with memory loss is a bit like "an old car that has broken down," he says. "But similar to repairing a car, you don't necessarily have to fix all parts, you have to find the key parts."

At least some of those parts are likely to be found in spinal fluid, Lehtinen says.

Her own lab has been studying the role of cerebrospinal fluid in the development of mouse brains.

"We found that the CSF delivers these important health and growth promoting factors that can, essentially, modulate brain growth," she says. "What's been lacking, so far, is the next step of testing whether these CSF factors can confer benefits to adult [brains]."

The new study suggests that they can, she says. [Copyright 2022 NPR]