Numerous studies conducted in mice and in humans have indicated that physical exercise can benefit the brain, for example, by slowing cognitive aging and neurodegeneration. A new study headed by Stanford School of Medicine researchers has now shown that it’s possible to transfer the brain benefits enjoyed by marathon-running mice to their couch-potato peers. The study demonstrated that blood from young adult mice that are getting lots of exercise, can benefit the brains of same-aged, sedentary mice.
The team compared blood samples from exercising and sedentary mice of the same age, and showed that transfusions of blood from running mice reduced neuroinflammation in the sedentary mice and improved their cognitive performance. The researchers isolated a single, blood-borne protein, clusterin (CLU), which appears to play an important role in the anti-neuroinflammatory effects of exercise. “We’ve discovered that this exercise effect can be attributed to a large extent to factors in the blood, and we can transfer that effect to a same-aged, non-exercising individual,” said Tony Wyss-Coray, PhD, the D. H. Chen Professor II, and senior author of the team’s paper, which is published in Nature.
The investigators suggest that their discovery could open the door to treatments that—by taming brain inflammation in people who don’t get much exercise—might lower their risk of neurodegenerative disease or slow its progression. Wyss-Coray, together with first author Zurine De Miguel, PhD, a former postdoctoral scholar in Wyss-Coray’s group, described their findings in a paper titled, “Exercise plasma boosts memory and dampens brain inflammation via clusterin.” In their report, they concluded, “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.” Wyss-Coray is a member of the Stanford Wu Tsai Neuroscience Institute, Stanford Bio-X, and the Stanford Maternal and Child Health Research Institute; and a faculty fellow of Stanford ChEM-H.
Physical exercise is generally beneficial to all aspects of human and animal health, and this extends to patients with neurodegeneration and brain trauma, possibly by reducing neuroinflammation, the authors wrote. Neuroinflammation has been strongly tied to neurodegenerative diseases in humans, said Wyss-Coray. Animal studies have indicated that neuroinflammation precipitates neurodegenerative disorders and that reversing or reducing neuroinflammation can prolong cognitive health.
Anybody who’s suffered from flu can relate to the loss of cognitive function that comes from a fever-inducing viral infection, Wyss-Coray said. “You get lethargic, you feel disconnected, your brain doesn’t work so well, you don’t remember as clearly.” That’s a result, at least in part, of the body-wide inflammation that follows the infection. As your immune system ramps up its fight, the inflammation spills over into your brain.
Neuroinflammation also exacerbates the progression of Alzheimer’s and other neurodegenerative diseases, said Wyss-Coray, a neuro-immunologist who in a study published earlier this year identified signs of brain inflammation in people who had died of COVID-19.
It’s already known that exercise induces a number of healthy manifestations in the brain, such as more nerve-cell production and less inflammation. However, the authors wrote, while “long-term voluntary exercise in mouse models of Alzheimer’s disease (AD) and related disorders improve learning and memory, and decrease neuroinflammation,” the team noted, exactly how exercise exerts these beneficial effects isn’t well understood.
Mice love to run. Give a caged mouse access to a running wheel a few inches in diameter and, with no training or prompting, it will rack up four to six miles a night (they sleep by day) on legs that are much shorter than ours. If you lock the wheel, the mouse won’t log nearly as much exercise, although it’s still free to skitter hither and thither about its cage (roughly equivalent to heading into the kitchen now and then to fetch a beer or a snack from the fridge).
The investigators put either functional or locked running wheels into the cages of three-month-old lab mice, which are metabolically equivalent to 25-year-old humans. A month of steady running was enough to substantially increase the quantity of neurons and other cells in the brains of these running, marathoner mice when compared with the brains of sedentary mice.
Next, the researchers collected blood from the exercising mice, and the control, sedentary mice. Then, every three days, they injected other sedentary mice with plasma from either the running mice (runner plasma; RP) or couch-potato, sedentary mice (control plasma; (CP). Each injection equaled 7% to 8% of the recipient mouse’s total blood volume. (An equivalent amount in humans would be about ½ to ¾ of a pint.)
On two different lab tests of memory, sedentary mice injected with the runner plasma outperformed their equally sedentary peers who received the control plasma. “… injection of RP, but not CP, increased the contextual learning and memory of mice in the fear conditioning paradigm without affecting their response to auditory cues, activity in a light–dark arena or anxiety levels in the activity chamber,” the team noted. “Similarly, RP improved their performance in the Morris water maze—a test of spatial learning and memory.” “The mice getting runner blood were smarter,” Wyss-Coray said. In addition, sedentary mice receiving plasma from the exercising mice had more cells that give rise to new neurons in the hippocampus (a brain structure associated with memory and navigation) than those animals given the control plasma transfusions.
The scientists compared activation levels of thousands of genes in the hippocampus of sedentary mice receiving either RP, or CP. Of the roughly 2,000 genes whose activation levels changed in response to runner plasma, the 250 of these differentially expressed genes (DEGs) whose activation levels changed most prominently were known to be most strongly linked to inflammatory processes, and their activation-level changes suggested lower neuroinflammation among mice who received the RP transfusions. “Interestingly, the top 250 DEGs pointed to a downregulation of the acute inflammatory response as the most significantly affected biological pathway …” the team noted.
“The runners’ blood was clearly doing something to the brain, even though it had been delivered outside the brain, systemically,” said Wyss-Coray. An examination of proteins in the runner animals’ blood identified 235 distinct proteins, of which 23 were scarcer and 26 more abundant in the exercising, versus the sedentary mice. Several of these differentially expressed proteins were associated with the complement cascade—a set of about 30 blood-borne proteins that interact with one another to kick-start the immune response to pathogens. “Biological pathway analysis pointed to activation of the alternative pathway of the complement system and endothelial cell differentiation,” the team stated. “Notably, proteins of the complement and coagulation pathways represent 26% of the significantly changed proteins.” Chronic inflammation resulting from aberrant activation of the complement system, Wyss-Coray noted, appears to accelerate the progression of many neurodegenerative disorders.
Removing a single protein, clusterin, from runner mouse plasma largely negated its anti-inflammatory effect on the sedentary mouse brain. Removing no other protein the scientists similarly tested – including complement factor H (FH), glycoprotein pigment epithelium-derived factor (PEDF) and leukemia inhibitor factor receptor (LIFR) – had the same effect. “Notably, the depletion of CLU largely abrogated the anti-inflammatory properties of RP, whereas depletion of FH, PEDF or LIFR had little or no effect,” they wrote. Clusterin, an inhibitor of the complement cascade, was significantly more abundant in the exercising animals’ blood than in the sedentary mouse blood.
Further experiments showed that clusterin binds to receptors that abound on brain endothelial cells, the cells that line the blood vessels of the brain. These cells are inflamed in the majority of Alzheimer’s patients, noted Wyss-Coray, whose research has shown that blood endothelial cells are capable of transducing chemical signals from circulating blood, including inflammatory signals, into the brain.
Further tests demonstrated that clusterin by itself, even though administered outside the brain, was able to reduce brain inflammation in two different strains of lab mice in which either acute bodywide inflammation, or Alzheimer’s-related chronic neuroinflammation, had been induced. “Intravenously injected CLU binds to brain endothelial cells and reduces neuroinflammatory gene expression in a mouse model of acute brain inflammation and a mouse model of Alzheimer’s disease.”
Separately, the investigators found that at the conclusion of a six-month aerobic exercise program, 20 military veterans with mild cognitive impairment—a precursor to Alzheimer’s disease—had elevated clusterin levels in their blood. These findings demonstrate the existence of anti-inflammatory exercise factors that are transferrable, target the cerebrovasculature and benefit the brain, and are present in humans who engage in exercise,” the investigators pointed out. Wyss-Coray speculated that a drug that enhances or mimics clusterin’s binding to its receptors on brain endothelial cells might help slow the course of neuroinflammation-associated neurodegenerative diseases such as Alzheimer’s.
