Paper Alert: Runners’ Plasma Calms Inflamed Mouse Brain

The health benefits of exercise are well-known, but might couch potatoes reap some of them through an infusion or even a pill? Researchers led by Tony Wyss-Coray, Stanford University, suggest so, at least in mice. In the December 8 Nature, they reported that blood taken from running mice conferred anti-inflammatory and memory-boosting effects of exercise to others that barely lifted a paw. The runners’ plasma even tempered inflammation in mice whose brains were full of amyloid. Clusterin, a complement-blocking apolipoprotein that ticks up in the blood after exercise, provided most of the benefit, the authors claim. Variants in the clusterin gene increase AD risk (Nov 2015 conference news; Jan 2014 news; Dec 2012 news). 

Adorning Blood Vessels. In mice recombinant clusterin (purple), bound hippocampal blood vessels (bottom).) In mice injected with just the fluorophore, vessels (green) stayed dark (top). [Courtesy of De Miguel et al., Nature, 2021.]

Alzforum first reported the findings when first author Zurine De Miguel and colleagues uploaded their paper to bioRxiv two years ago (Sep 2019 news). Then, it was unclear if plasma clusterin crossed the blood-brain barrier or how it might help the brain. The scientists suspected it may interact with the cerebrovasculature, given that brain endothelial cells highly express the clusterin receptor apolipoprotein E receptor 2.

Now, in Nature, the researchers confirm that clusterin’s anti-inflammatory prowess stems from its binding to those endothelial cells, which turn down expression of inflammatory proteins. De Miguel injected recombinant clusterin labeled with the fluorophore A-647N into 3-month-old C57BL/6J mice. Lo and behold, this clusterin lit up blood vessels in the hippocampus (see image above).

Flipping Inflammation. Of 20 genes upregulated in hippocampal endothelial cells from APP mice (top row), all became downregulated after a peripheral injection of recombinant clusterin (bottom row). [Courtesy of De Miguel et al., Nature, 2021.]

Together, the findings suggest that clusterin in the blood is able to dial down both chronic and acute neuroinflammation, the authors conclude.—Chelsea Weidman Burke

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References

Alzpedia Citations

  1. Clusterin

News Citations

  1. Alzheimer’s Risk Genes Give Up Some Secrets at SfN
  2. Does Clusterin Interact With Aβ to Kick Off Neurodegeneration?
  3. Getting a CLU—Does Genetic Risk Factor Mediate Aβ Toxicity?
  4. 'Runner Plasma' Jogs Neurogenesis, Quells Neuroinflammation in Mice

Further Reading

Primary Papers

  1. De Miguel Z, Khoury N, Betley MJ, Lehallier B, Willoughby D, Olsson N, Yang AC, Hahn O, Lu N, Vest RT, Bonanno LN, Yerra L, Zhang L, Saw NL, Fairchild JK, Lee D, Zhang H, McAlpine PL, Contrepois K, Shamloo M, Elias JE, Rando TA, Wyss-Coray T. Exercise plasma boosts memory and dampens brain inflammation via clusterin. Nature. 2021 Dec;600(7889):494-499. Epub 2021 Dec 8 PubMed.

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