Exercise plasma dampens brain inflammation via clusterin and boosts memory

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 “runner” plasma, collected from voluntarily running mice, infused into sedentary mice recapitulates the cellular and functional benefits of exercise on the adult brain. Importantly, runner plasma reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation. Plasma proteomic analysis revealed a striking increase in complement cascade inhibitors including clusterin (CLU), which is facilitating 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 Alzheimer’s disease model mice. Cognitively impaired patients participating in structured exercise for 6 months showed improved cognition and 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.