Blood From Active Mice Appears to Benefit Brains of Sedentary Peers

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by Patricia Inacio, PhD |

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Blood from “runner” mice can boost cognition and memory, and lessen brain inflammation — a key feature seen in people with neurodegenerative diseases, such as Alzheimer’s — when transferred into sedentary mice, a study shows.

The benefits of “exercised” blood was linked to high levels of the clusterin protein, an inhibitor of the complement signaling pathway, which is a key part of the immune system previously associated with neuroinflammation.

These findings show that the anti-inflammatory potential of exercise is carried in the blood and is mediated by certain blood-carrying proteins. This may lead to the development of new therapies to lessen brain inflammation and improve cognition.

The study, “Exercise plasma boosts memory and dampens brain inflammation via clusterin,” was published in the journal Nature.

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Physical exercise is known to induce certain bodily responses across different tissues and improve human health. These benefits also apply to those with neurodegenerative diseases and brain trauma, as exercise is likely to lessen brain inflammation.

In previous studies, long-term exercise in mouse models of Alzheimer’s was found to improve learning and memory as well as decrease neuroinflammation. The cognitive benefits of physical exercise are likely linked to its effects on the brain’s hippocampus, which plays a role in learning, memory, and spatial navigation.

“It has been proposed that ‘exercise factors’ — secreted from muscle and other tissues into the blood — subsequently signal to the brain,” the researchers wrote. “However, it is unknown whether exercise-conditioned plasma contains factors that benefit the young healthy brain, whether these factors are directly transferrable through the plasma, whether such factors mediate the anti-inflammatory effect of exercise and what the key factors are.”

In the new study, researchers at Stanford School of Medicine set out to understand the effects of transferring blood plasma from exercising male mice into young non-exercising mice.

The team used mice that were 3 months old — equivalent to 25 years in humans — and that had access to either working or locked running wheels in their cages. Mice without access to a running wheel were used as controls.

Running for 28 days was enough to boost the survival of neurons and other cells in the brains of running mice when compared with those of non-running (sedentary) mice.

The researchers went on to show that blood collected from running mice and transferred, every three days, to age- and sex-matched sedentary mice lessened inflammation in the brain and boosted their cognitive performance, when compared to blood transferred from control mice.

“The mice getting runner blood were smarter,” Tony Wyss-Coray, PhD, professor of neurology and neurological sciences, and the study’s senior author, said in a Stanford press release.

Also, sedentary mice given blood from running mice had an increased number of progenitor nerve cells in their brain hippocampus, compared to control mice.

The researchers profiled genes in the hippocampus of sedentary mice that had been treated with blood from running mice and observed that, compared to controls, the activity of roughly 2,000 genes had changed. The top 250 genes were linked to inflammatory processes, and changes in their activation levels suggested a reduction in neuroinflammation.

“The runners’ blood was clearly doing something to the brain, even though it had been delivered outside the brain, systemically,” said Wyss-Coray.

The researchers then profiled the blood of running mice and detected changes in 235 blood proteins. Several of these proteins were associated with the complement system — a set of more than 30 blood proteins that form part of the body’s immune defenses.

Chronic aberrant activation of the complement system may drive neuroinflammation and has been linked with the accelerated progression of many neurodegenerative disorders, Wyss-Coray said.

One of the top complement-related proteins with altered levels was clusterin, which was previously linked to Alzheimer’s disease in a 2009 study. Clusterin was present at significantly higher levels in the blood of running mice than in that of control mice.

To assess clusterin’s potential, the researchers removed it only from the blood of running mice and observed that the anti-inflammatory effect on sedentary mice’s brains was no longer visible. No other protein the scientists tested had the same effect.

Further experiments showed that clusterin could bind to receptors located at the surface of brain endothelial cells, the cells that line the blood vessels of the brain. Previous work from Wyss-Coray’s lab showed that endothelial cells from Alzheimer’s patients are inflamed and are capable of releasing inflammatory signals into the brain.

Infusion of clusterin by itself was able to reduce brain inflammation in two different types of mice, one with acute, whole-body inflammation and another with Alzheimer’s-related chronic neuroinflammation.

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To assess if these findings would be important to humans, the researchers conducted a preliminary experiment where they measured the levels of clusterin in 20 military veterans with mild cognitive impairment before and after they underwent a six-month aerobic exercise program.

The results showed that the levels of clusterin in the blood were significantly elevated after exercise.

“Collectively, the findings presented here provide new insights into the mechanisms of how exercise benefits the brain,” the researchers wrote.

“Our results offer new paths to develop therapies based on proteins that are induced by exercise that have the ability to reduce neuroinflammation and improve cognitive function,” they concluded.