Regular exercise infuses the blood with factors that benefit the brain, according to a manuscript posted on the bioRχiv preprint server on September 19. Researchers led by Tony Wyss-Coray of Stanford University reported that plasma taken from mice with access to a running wheel improved neurogenesis and quelled harmful neuroinflammation seen in sedentary mice. “Runner plasma” contained inhibitors of coagulation and complement pathways, including clusterin, a known Alzheimer’s disease risk gene, that imparted many of the anti-inflammatory benefits. Plasma clusterin levels rose in people with mild cognitive impairment when they, too, exercised regularly. Alzforum summarized some of the preliminary findings when presented at a Keystone symposium last year (Jul 2018 conference news).
- Plasma from exercising mice boosted neurogenesis and reduced neuroinflammation in sedentary mice.
- Running increased complement inhibitors in plasma, including clusterin.
- Exercise raised clusterin levels in people with mild cognitive impairment.
“These findings are consistent with recent studies showing that peripheral factors secreted from muscle, liver, and fat tissues during exercise may mediate the beneficial effects of physical activity on the brain,” wrote Henriette van Praag of Florida Atlantic University in Jupiter.
Exercise induces profound changes across multiple organs of the body, including the brain. Human studies have suggested that regular physical activity boosts cognition and may even counteract neurodegenerative disease (Jan 2019 news; Jul 2019 conference news; Aug 2019 news). In mouse models of aging and neurodegenerative disease, exercise reportedly promotes the birth of newborn neurons, quells neuroinflammation, and counteracts cognitive decline (van Praag et al., 1999; May 2002 news; Mar 2005 conference news; Tapia-Rojas et al., 2015). Exactly how exercise benefits the brain, however, is unclear. Wyss-Coray hypothesized that systemic factors might drive the effects, on par with the brain-rejuvenating powers of plasma from young mice that he and other researchers had previously discovered (May 2014 conference news; Dec 2018 conference news).
Co-first authors Zurine De Miguel and Michael Betley first established direct effects of exercise on neurogenesis. When they placed a running wheel in mouse cages for 28 days, the mice had significantly more newborn neurons in the hippocampus, more proliferation of neural progenitor cells, and more neurons and astrocytes survived, as has been reported previously. Mice given a locked running wheel did not have these effects.
Runner Plasma Births Neurons. Plasma from running or sedentary mice was transferred into age-matched recipients once every three days for one month. Recipients of “runner plasma” had more doublecortin-positive neuroblasts (bottom right). [Courtesy of De Miguel et al., BioRχiv, 2019.]
Would plasma from running mice bestow these same benefits to sedentary mice? The researchers found that, over a period of 28 days, injecting plasma pooled from running males boosted overall cell proliferation in the hippocampi of sedentary male mice by a third, and the number of neuroblasts by 40 percent. Regular infusions of runner plasma also bolstered the survival of neural progenitor cells, promoted their maturation into mature neurons, and supported survival of newborn astrocytes. Runner plasma, but not control plasma, also appeared to improved learning and memory, as gauged by freezing behavior when mice were placed in a cage where they had previously received a foot shock.
What underpins these effects of runner plasma? To investigate, the researchers sequenced RNA from the hippocampi of the mice. They found nearly 2,000 differentially expressed genes, of which 61 percent were turned down and 39 percent turned up, in mice that received runner rather than control plasma. Among the 250 most differentially expressed genes, the acute inflammatory response emerged as the most downregulated cellular function, followed by proteolysis. Cell junction organization was the most elevated functional pathway.
Runner plasma even appeared to reverse the dramatic pro-inflammatory response to systemic treatment with lipopolysaccharide. Eight hours after intravenous injection of this bacterial endotoxin, nearly 5,000 genes changed expression in the hippocampus. However, when animals were injected with runner plasma four hours after the LPS, a majority of these gene expression changes did not happen.
Which ingredients in runner plasma deliver this benefit? To find out, the scientists subjected pooled plasma to mass spectrometry. Of 235 proteins that were detectable, 49 were elevated or reduced in runner compared with control plasma. Proteins involved in the complement cascade or coagulation—two pathways that often move in lockstep—made up a quarter of the differentially expressed proteins. Clusterin, an apolipoprotein with multiple functions including inhibition of complement, was higher in runner plasma, as was the complement inhibitor Factor H. Interestingly, the researchers found that depleting clusterin from runner plasma strongly diminished its anti-inflammatory properties. Infusing clusterin-less runner plasma into LPS-treated mice did little to dampen the subsequent inflammatory response. The findings suggested that clusterin is a key factor in runner plasma that quells neuroinflammation.
Would exercise similarly boost clusterin in people? The researchers compared the plasma proteomes of 20 veterans—19 men, one woman—with amnestic mild cognitive impairment before and after they participated in a six-month exercise regimen. Plasma clusterin was higher, while other complement proteins were lower, after the program, which consisted of combined aerobic and resistance training for one hour three times per week. More broadly, changes in clusterin appeared to associate with changes in proteins involved with regulation of the immune response. Clusterin levels also rose in step with improvements in aerobic capacity and endurance. The researchers did not have cognitive data.
De Miguel told Alzforum that together, the findings suggest that exercise induces systemic changes that impact brain physiology, including promoting neurogenesis and keeping damaging neuroinflammation at bay. She is continuing to dissect the mechanisms involved. In regard to clusterin, De Miguel is investigating how exercise stimulates its release from cells that lie outside the brain, including hepatocytes (Sep 2009 news). She noted that while clusterin may cross the blood-brain barrier, it might also influence the brain by interacting with the endothelial cells that line blood vessels. Other researchers recently described just such an outside-in effect, showing VCAM1 in brain endothelium mediated damaging brain effects of aged plasma (May 2019 news). Wyss-Coray’s group is hunting for cells in the brain that may respond to clusterin or other exercise-induced proteins that cross the blood-brain barrier.
In Alzheimer’s and other neurodegenerative diseases, overzealous pruning of synapses by complement-triggered pathways is thought to wreak havoc. De Miguel thinks it is possible that an exercise-induced boost in plasma clusterin could counteract such pruning. Interestingly, a previous study found that exercise tempered the elevation of AD biomarkers in carriers of clusterin, ApoE, and ABCA7 variants linked to AD (Aug 2015 conference news).
Still, clusterin is more than a complement inhibitor. This apolipoprotein plays a role in cholesterol metabolism, binds Aβ, and even reportedly stimulates neurogenesis (Jan 2014 news). Van Praag proposed that researchers explore the latter. “Maybe it could be assessed if clusterin plays a direct role in adult hippocampal neurogenesis and memory function in mouse models, and if adult-born hippocampal neurons express receptors that may bind clusterin,” she wrote.
“Overall, these results further support the potency of exercise as a strategy to promote brain health,” commented Teresa Liu-Ambrose of the University of British Columbia in Vancouver, Canada. However, she noted that biological sex moderates the effect of exercise on the brain, hence it will be important to repeat these studies in female mice and in far more than one woman.
Rong Zhang of the University of Texas Southwestern Medical Center in Dallas agreed that the findings need to be extended into females. He noted that the ongoing Molecular Transducers of Physical Activity Consortium, a six-year trial that aims to track molecular changes evoked by physical activity, could help confirm whether complement inhibitors, including clusterin, ramp up in response to exercise. If so, the findings could point the way to new therapeutic targets to slow brain aging and prevent neurodegenerative disease, he wrote.—Jessica Shugart
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- van Praag H, Kempermann G, Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci. 1999 Mar;2(3):266-70. PubMed.
- Tapia-Rojas C, Aranguiz F, Varela-Nallar L, Inestrosa NC. Voluntary Running Attenuates Memory Loss, Decreases Neuropathological Changes and Induces Neurogenesis in a Mouse Model of Alzheimer's Disease. Brain Pathol. 2015 Mar 11; PubMed.
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- De Miguel Z, Betley MJ, Willoughby D, Lehallier B, Olsson N, Bonanno L, Fairchild KJ, Contrepois K, Elias JE, Rando TA, Wyss-Coray T. Exercise conditioned plasma dampens inflammation via clusterin and boosts memory. bioRxiv September 19, 2019. BioRxiv.