Exercise plasma boosts memory and dampens brain inflammation via clusterin

Zurine Miguel, Nathalie Khoury, Michael J. Betley, Benoit Lehallier, Drew Willoughby, Niclas Olsson, Andrew C. Yang, Oliver Hahn, Nannan Lu, Ryan T. Vest, Liana N. Bonanno, Lakshmi Yerra, Lichao Zhang, Nay Lui Saw, J. Kaci Fairchild, Davis Lee, Hui Zhang, Patrick L. McAlpine, Kévin Contrepois, Mehrdad Shamloo, Joshua E. Elias, Thomas A. Rando and Tony Wyss-Coray ()
Additional contact information
Zurine Miguel: Stanford University School of Medicine
Nathalie Khoury: Stanford University School of Medicine
Michael J. Betley: Stanford University School of Medicine
Benoit Lehallier: Stanford University School of Medicine
Drew Willoughby: Stanford University School of Medicine
Niclas Olsson: Stanford University School of Medicine
Andrew C. Yang: Stanford University School of Medicine
Oliver Hahn: Stanford University School of Medicine
Nannan Lu: Stanford University School of Medicine
Ryan T. Vest: Stanford University School of Medicine
Liana N. Bonanno: Stanford University School of Medicine
Lakshmi Yerra: The Veterans Affairs Palo Alto HealthCare System
Lichao Zhang: Chan Zuckerberg Biohub
Nay Lui Saw: Stanford University School of Medicine
J. Kaci Fairchild: The Veterans Affairs Palo Alto HealthCare System
Davis Lee: Stanford University School of Medicine
Hui Zhang: Stanford University School of Medicine
Patrick L. McAlpine: Stanford University
Kévin Contrepois: Stanford University
Mehrdad Shamloo: Stanford University School of Medicine
Joshua E. Elias: Stanford University School of Medicine
Thomas A. Rando: Stanford University School of Medicine
Tony Wyss-Coray: Stanford University School of Medicine

Nature, 2021, vol. 600, issue 7889, 494-499

Abstract: Abstract Physical exercise is generally beneficial to all aspects of human and animal health, slowing cognitive ageing and neurodegeneration1. The cognitive benefits of physical exercise are tied to an increased plasticity and reduced inflammation within the hippocampus2–4, yet little is known about the factors and mechanisms that mediate these effects. Here we show that ‘runner plasma’, collected from voluntarily running mice and infused into sedentary mice, reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation. Plasma proteomic analysis revealed a concerted increase in complement cascade inhibitors including clusterin (CLU). 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. Patients with cognitive impairment who participated in structured exercise for 6 months had higher plasma levels of CLU. 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.

Date: 2021
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DOI: 10.1038/s41586-021-04183-x

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