How gym junkie mice could inspire a new therapy for dementia
We know exercise is good for the brain, but we don’t know exactly how exercise improves brain health. A new Stanford study has homed in on a single anti-inflammatory protein that seems to increase in the blood with exercise and the findings could inspire new kinds of drugs that prevent neurodegeneration or cognitive decline.
Around a decade ago Tony Wyss-Coray and a team of Stanford University scientists discovered infusing blood from young mice into older mice seemed to improve the aging animals cognitive capacities. The findings spawned a number of controversial “young blood” start-ups offering infusions of plasma to curious rich people willing to pay thousands of dollars for the experimental treatment.
More recently Wyss-Coray’s research has focused on the links between neuroinflammation and neurodegenerative disease. Earlier this year his team published a key study on the link between COVID-19 and brain inflammation.
This latest study, published in the journal Nature, focuses on how exercise can prompt the release of anti-inflammatory molecules that improve brain health. And the investigations again started with blood transfusion experiments in mice.
The researchers first looked at two groups of mice. One group was given free rein to run on exercise wheels for a month while the other group had their exercise wheel locked for the same period of time. After a month the researchers noted the exercising mice displayed greater volumes of hippocampal neurons compared to the sedentary mice.
A third group of mice were also kept stationary for a month and then offered blood plasma transfusions from either the exercising or sedentary mice. Impressively, the mice receiving the runner blood performed better in cognitive tests compared to animals receiving the couch-potato blood.
“The mice getting runner blood were smarter,” says Wyss-Coray. “The runners’ blood was clearly doing something to the brain, even though it had been delivered outside the brain, systemically.”
So what was different in the blood of the exercising mice compared to the sedentary mice?
A similar study published last year from UC San Francisco researchers zeroed in on an exercise-induced protein called Gpld1, but this Stanford study suggests a different molecular culprit. From a short-list of more than 200 proteins distinguishing the exercising blood from the sedentary blood, a single protein quickly stood out – clusterin.
Following on from Wyss-Coray’s prior investigations into the deleterious effect of neuroinflammation on cognition, the new research found most of the key protein differences between the two types of mouse blood were related to inflammatory processes. And clusterin in particular seemed to play a major anti-inflammatory role.
When clusterin was removed from the runner blood most of the brain health benefits were not apparent after transfusion into sedentary animals. And more specifically, when the researchers administered clusterin by itself to strains of mice engineered to model neuroinflammation they saw reductions in signs of brain inflammation.
Finally the researchers looked to a cohort of humans to validate their findings. Data was analyzed from a separate study looking at the effect of a six-month exercise program on 20 veterans with mild cognitive impairment. At the end of the intervention the researchers found those subjects exercising three times a week showed increased levels of clusterin in their blood and improvements on memory tests.
Madhav Thambisetty, a researcher from the National Institute of Aging who has studied clusterin and did not work on this new study, says the findings are interesting but do not suggest this particular protein is a magic treatment for neurodegeneration. A previous study from Thambisetty found clusterin levels can be elevated in patients suffering from Alzheimer’s disease, sometimes for years before symptoms of cognitive decline even become apparent.
“It’s far too premature to conclude that higher or lower levels of clusterin might be either beneficial or not,” Thambisetty recently told the New York Times. “I don’t think we’re at the stage yet where people can trade in their treadmills or cancel their gym memberships for a clusterin pill or a clusterin injection.”
Addressing this prior finding in the new study Wyss-Coray and colleagues hypothesize these heightened clusterin plasma levels in human subjects with Alzheimer’s as a possible compensatory mechanism. As if the body is raising clusterin levels to push back on other inflammatory mechanisms relating to neurodegeneration.
Wyss-Coray doesn’t suggest clusterin itself could be a future treatment for cognitive decline. Instead, he speculates further work into exactly what this exercise-induced protein is actually doing to the brain could inform the development of novel molecules that specifically hijack this mechanism. And through this understanding researchers could potentially develop new treatments to reduce neuroinflammation and prevent cognitive decline.
The new study was published in the journal Nature.
Source: Stanford Medicine