Exercise plasma boosts memory and dampens brain inflammation via clusterin

Zurine De 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; Tony Wyss-Coray

doi:10.1038/s41586-021-04183-x

Exercise plasma boosts memory and dampens brain inflammation via clusterin

Nature. 2021 Dec;600(7889):494-499. doi: 10.1038/s41586-021-04183-x. Epub 2021 Dec 8.

Authors

Zurine De Miguel^{1

2

3

4}, Nathalie Khoury^#^{1

2

3}, Michael J Betley^#^{1

5}, Benoit Lehallier^{1

2

3

6}, Drew Willoughby^{1

2

3}, Niclas Olsson^{7

8}, Andrew C Yang^{1

2

3}, Oliver Hahn^{1

2

3}, Nannan Lu^{1

2

3}, Ryan T Vest^{1

2

3}, Liana N Bonanno^{1

2

3}, Lakshmi Yerra⁹, Lichao Zhang¹⁰, Nay Lui Saw¹¹, J Kaci Fairchild⁹, Davis Lee^{1

2

3}, Hui Zhang^{1

2

3}, Patrick L McAlpine¹², Kévin Contrepois¹³, Mehrdad Shamloo¹¹, Joshua E Elias^{7

10}, Thomas A Rando^{1

2

9}, Tony Wyss-Coray^{14

15

16}

Affiliations

¹ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
² Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA.
³ Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
⁴ Psychology Department, California State University, Monterey Bay, CA, USA.
⁵ Neurosciences Graduate Training Program, Stanford University School of Medicine, Stanford, CA, USA.
⁶ Alkahest Inc, San Carlos, CA, USA.
⁷ Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
⁸ Calico Life Sciences, South San Francisco, CA, USA.
⁹ The Veterans Affairs Palo Alto HealthCare System, Palo Alto, CA, USA.
¹⁰ Chan Zuckerberg Biohub, Stanford, CA, USA.
¹¹ Behavioral and Functional Neuroscience Laboratory, Stanford University School of Medicine, Stanford, CA, USA.
¹² Otolaryngology Head and Neck Surgery Research Division, Stanford University, Stanford, CA, USA.
¹³ Department of Genetics, Stanford University, Stanford, CA, USA.
¹⁴ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. twc@stanford.edu.
¹⁵ Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA. twc@stanford.edu.
¹⁶ Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. twc@stanford.edu.

^# Contributed equally.

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 hippocampus^2-4, 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alzheimer Disease* / metabolism
Animals
Clusterin / genetics
Clusterin / metabolism
Encephalitis*
Endothelial Cells / metabolism
Humans
Mice
Proteomics

Substances

Clusterin

Abstract

Publication types

MeSH terms

Substances

Grants and funding