Exercise plasma boosts memory and dampens brain inflammation via clusterin

Physical exercise seems universally beneficial to human and animal health, slowing cognitive aging and neurodegeneration. Cognitive benefits are tied to increased plasticity and reduced inflammation within the hippocampus, yet little is known about the factors and mechanisms mediating these effects. We discovered 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), a central protein for the anti-inflammatory effects of runner plasma. Intravenously injected CLU strongly binds to brain endothelial cells reducing their inflammatory gene expression in an acute model of brain inflammation and in an Alzheimer’s disease mouse model. Cognitively impaired patients participating in structured exercise for 6 months had higher plasma clusterin levels. 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 engaging in exercise.