Exercise conditioned plasma dampens inflammation via clusterin and boosts memory

Abstract

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 brain. Importantly, runner plasma reduces baseline neuroinflammatory gene expression and prominently suppresses experimentally induced brain inflammation. Plasma proteomic analysis shows a striking increase in complement cascade inhibitors including clusterin, which is necessary for the anti-inflammatory effects of runner plasma. Cognitively impaired patients participating in structured exercise for 6 months showed higher plasma clusterin levels, which correlated positively with improvements in endurance and aerobic capacity. These findings demonstrate the existence of anti-inflammatory "exercise factors" that are transferrable, benefit the brain, and are present in humans engaging in exercise.Physical activity evokes profound physiological responses in multiple tissues in species from fish, to birds, rats, mice and humans 1-6 . It is widely accepted and promoted as a method of improving human health, including brain health 7-9 . Exercise interventions in people of various ages with or without neurodegenerative diseases, or brain damage, have been shown to improve cognitive function 9,10,11,12 . Neuroinflammation is a common feature of these conditions and potential mediator of the cognitive impairment associated with them [13][14][15][16] . Studies in mouse models of aging and neurodegenerative diseases, such as AD and Parkinson disease have linked long-term voluntary wheel running with improved learning and memory, and decreased neuroinflammation 17-20 . However, how exercise exerts these beneficial effects on the brain is poorly understood. It is possible that the physical exertion of muscle or lung during exercise may result in the secretion of factors from these or other tissues which subsequently signal to the brain to reduce neuroinflammation. Indeed, physical exercise increases levels of dozens of proteins in plasma, many of which are likely released from muscle tissue and thus named myokines 2,21 . Some of these myokines, such as insulin-like growth factor-1 (IGF-1) 22 , vascular endothelial growth factor (VEGF) 23 and platelet factor 4 (PF4) 24 increase following exercise and have been shown to increase hippocampal neurogenesis (Extended Table 1). However, it is unknown whether exercise conditioned plasma contains the factors benefitting the brain, whether these factors are directly transferrable through plasma, how such factors impact the brain, and what the key factors are. Runner plasma infusions induce neuroplasticity, improve learning and memory and regulate transcription of genes associated with the acute inflammatory response in the h...

Microglial Correlates of Late Life Physical Activity: Relationship with Synaptic and Cognitive Aging in Older Adults

“…It is possible that we did not fully capture other forms of microglial activation not reflected by HLA isoforms. Additionally, the precise molecular cascade through which physical activity promotes microglial homeostasis is not clear, although complement and coagulation signaling are highly implicated (De Miguel et al, 2019;Horowitz et al, 2020). Both models estimated indirect effects of PAM IT (mediation) conditional on AD pathology burden (moderation) using 5000-sample bootstrapping.…”

Exercise increases information content and affects long-term stability of hippocampal place codes

“…The mechanisms by which physical activity aids hippocampal cognition and memory involve multiple factors, acting systemically and locally within the brain. These include an increase in neurotrophic factors ( Neeper et al., 1995 ; Cotman and Berchtold, 2002 ; Vaynman et al., 2003 , 2004 ; Liu et al., 2008 ; Rasmussen et al., 2009 ; Griffin et al., 2011 ; Marlatt et al., 2012 ; Sleiman et al., 2016 ), changes in neurotransmitters and their receptors ( Fordyce and Farrar, 1991a ; Gómez-Pinilla et al., 1997 ; Carro et al., 2000 ; Farmer et al., 2004 ; Fisher et al., 2013 ; Moon et al., 2016 ), vasculature alterations ( Swain et al., 2003 ; Lopez-Lopez et al., 2004 ; Maass et al., 2015 ), increased dendritic spine density ( Stranahan et al., 2007 ), reduced inflammation ( de Miguel et al., 2021 ), and enhanced synaptic plasticity ( O’Callaghan et al., 2007 ). One of the prominent effects of exercise is enhanced neurogenesis in the adult hippocampal dentate gyrus ( van Praag et al., 1999a , 1999b ; Wu et al., 2008 ), which, in turn, improves spatial and contextual discrimination ( Clelland et al., 2009 ; Creer et al., 2010 ; Sahay et al., 2011a ).…”

Constitutive PGC-1α Overexpression in Skeletal Muscle Does Not Contribute to Exercise-Induced Neurogenesis

“…In a study by De Miguel and colleagues, plasma from voluntary running 3-month-old mice injected in age-matched sedentary animals resulted in increased hippocampal neurogenesis and improvement in memory and learning [77]. This effect was most pronounced with plasma from 28day-runners which increased cell proliferation, survival and neuroblast count, whereas plasma from 7-and 14-dayrunners only resulted in an increased neuroblast count.…”