Physical activity and exercise attenuate neuroinflammation in neurological diseases

Accepted Manuscript Title: Physical activity and exercise attenuate neuroinflammation in neurological diseases Author: Lindsay Joy Spielman Jonathan Peter Little Andis Klegeris PII: DOI: Reference:

S0361-9230(16)30055-7 http://dx.doi.org/doi:10.1016/j.brainresbull.2016.03.012 BRB 8984

To appear in:

Brain Research Bulletin

Received date: Revised date: Accepted date:

24-11-2015 17-3-2016 22-3-2016

Please cite this article as: Lindsay Joy Spielman, Jonathan Peter Little, Andis Klegeris, Physical activity and exercise attenuate neuroinflammation in neurological diseases, Brain Research Bulletin http://dx.doi.org/10.1016/j.brainresbull.2016.03.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Physical activity and exercise attenuate neuroinflammation in neurological diseases.

Lindsay Joy Spielmana, Jonathan Peter Littleb, Andis Klegerisa*

a

Department of Biology, University of British Columbia Okanagan Campus,

3187 University Way, Kelowna, BC, Canada V1V 1V7 b

School of Health and Exercise Sciences, University of British Columbia Okanagan

Campus, 1147 Research Road, Kelowna, BC, Canada V1V 1V7

*

Corresponding author: Tel.: +1 250 807 9557; Fax: +1 250 807 8830.

Email addresses: [email protected] (L.J. Spielman), [email protected] (J.P. Little), [email protected] (A. Klegeris).

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Graphical Abstract

Highlights 

A physically active lifestyle reduces the risk of developing brain diseases

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Exercise and physical activity have whole body anti-inflammatory effects

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Exercise may be neuroprotective due to a reduction in neuroinflammation

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Exercise intervention can reduce neuroinflammation in brain disease and improve prognosis

ABSTRACT Major depressive disorder (MDD), schizophrenia (SCH), Alzheimer’s disease (AD), and Parkinson’s disease (PD) are devastating neurological disorders, which increasingly

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contribute to global morbidity and mortality. Although the pathogenic mechanisms of these conditions are quite diverse, chronic neuroinflammation is one underlying feature shared by all these diseases. Even though the specific root causes of these diseases remain to be identified, evidence indicates that the observed neuroinflammation is initiated by unique pathological features associated with each specific disease. If the initial acute inflammation is not resolved, a chronic neuroinflammatory state develops and ultimately contributes to disease progression.

Chronic neuroinflammation is

characterized by adverse and non-specific activation of glial cells, which can lead to collateral damage of nearby neurons and other glia. This misdirected neuroinflammatory response is hypothesized to contribute to neuropathology in MDD, SCH, AD, and PD. Physical activity (PA), which is critical for maintenance of whole body and brain health, may also beneficially modify neuroimmune responses. Since PA has neuroimmunemodifying properties, and the common underlying feature of MDD, SCH, AD, and PD is chronic neuroinflammation, we hypothesize that PA could minimize brain diseases by modifying glia-mediated neuroinflammation. This review highlights current evidence supporting the disease-altering potential of PA and exercise through modifications of neuroimmune responses, specifically in MDD, SCH, AD and PD. Abbreviations: 5-HT, serotonin; AA, arachidonic acid; Aβ, amyloid beta protein; AD, Alzheimer’s disease; AGE, advanced-glycation end product; BBB, blood brain barrier; BDNF, brain-derived neurotrophic factor; CD, cluster of differentiation, CNS, central nervous system; COX, cyclooxygenase; CRP, C-reactive protein; DA, dopamine; DAMPs, damage-associated molecular patterns; GDNF, glial cell line derived neurotrophic factor; GFAP, glial fibrillary acidic protein; Glu, glutamate; HSP, heat shock protein; ICAM1, intercellular adhesion molecule 1; IL, interleukin; IL-1ra, IL-1 receptor antagonist; IFN, interferon; IGF, insulin-like growth factor; iNOS, inducible nitric oxide synthase; KAT, kynurenine aminotransferases; LOX, lipopolysaccharide; LPS, lipoxygenase; LTP, long-term potentiation; M1, pro-inflammatory phenotype of macrophages; M2, anti-inflammatory phenotype of macrophages; MAC, macrophage antigen complex; MCP, monocyte chemotactic protein; MDD, major depressive disorder; MHC, major histocompatibility complex; MWM, Morris water maze; NFκB, nuclear

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factor kappa B; NFT, neurofibrillary tangle; NGF, nerve growth factor; NSAID, nonsteroidal anti-inflammatory drug; NT, neurotrophin; PA, physical activity; PD, Parkinson’s disease; PGC, peroxisome proliferator-activated receptor gamma coactivator; ROS, reactive oxygen species; SCH, schizophrenia; T2DM, type 2 diabetes mellitus; TLR, toll-like receptor; TNF, tumor necrosis factor; UPDRS, Unified Parkinson’s Disease Rating Scale; VCAM, vascular cell adhesion molecule; VGNF, vascular endothelial growth factor; VWR, voluntary wheel running. Keywords: Alzheimer’s disease, exercise, major depressive disorder, Parkinson’s disease, schizophrenia, sedentary lifestyle 1. Introduction It is universally accepted that physical activity (PA) is crucial for maintaining a healthy body. The whole-body benefits of both PA (a consistent routine of body movement that burns calories) and exercise (a subcategory of PA that includes planned, structured and repetitive activity aimed towards enhanced muscular tone or endurance abilities) are well known (Center for Disease Control and Prevention, 2015). Although PA and exercise are defined differently, their outcomes frequently overlap, often achieving a similar overall effect.

The effects of PA and exercise can include increased

cardiovascular endurance and capacity, enhanced muscular tone, increased muscular strength, improved metabolism, and decreased adiposity (Bergman, 2013; Egan and Zierath, 2013; Fiuza-Luces et al., 2013; Peixoto et al., 2015; Stewart et al., 2005; Stojanovic et al., 2012). PA also has beneficial effects in the brain such as improved mood and mental health, as well as enhanced memory and cognitive abilities (Moore et al., 2014; Roig et al., 2013). Recent evidence shows that in addition to modifying cardiovascular, muscular and endocrine systems, both acute and chronic exercise have immune-modifying properties, which can lead to an overall whole-body antiinflammatory effect (Flynn and McFarlin, 2006; Gleeson et al., 2011; Pedersen, 2006; Stewart et al., 2005). The extent to which PA and exercise modify immune responses is just developing, with an emerging focus on the potential immune-modifying effects of

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exercise in the brain. The purpose of this review is to summarize the published data on the immune-modifying effects of PA in the brain. We will focus on the neuroimmune effects of PA in the central nervous system (CNS) and highlight the use of exercise as a possible therapeutic option for those suffering from major depressive disorder (MDD), schizophrenia (SCH), Alzheimer’s disease (AD) and Parkinson’s disease (PD), since each of these pathologies has a neuroinflammatory component.

2. Anti-inflammatory effects of physical activity and exercise in the periphery The innate immune system is the body’s major defense system, which is necessary for fighting exogenous pathogens and eliminating any resulting infections. However, the innate immune system can also be activated in the absence of infection in response to endogenous danger signals, such as necrotic cellular debris and damageassociated molecular patterns (DAMPs) (Dheen et al., 2007). Once the immune system has recognized either exogenous or endogenous triggers, the process of inflammation works to neutralize and eliminate the foreign and/or damaging substances from our bodies, through processes such as cytokine and nitric oxide release, antigen presentation, and phagocytosis (Block et al., 2007; Frank-Cannon et al., 2009; Lull and Block, 2010). This important inflammatory mechanism is followed by tissue repair and resolution of pro-inflammatory reactions in order to return the body to its homeostatic state. Although an active immune system is critical for maintaining health, an overactive immune system can lead to chronic inflammation, which can have very detrimental effects due to its non-specific nature. For example, several lifestyle-related conditions, including obesity, type 2 diabetes mellitus (T2DM), and lack of PA, are accompanied by chronic activation of the immune system, which leads to a systemic proinflammatory state (Spielman et al., 2014; Tucsek et al., 2014). PA and exercise have the potential to reduce and revert some of the immune activation associated with these behaviors, returning the body to a healthy state (Gaesser, 2007). Recent studies have unveiled that PA may contribute to an anti-inflammatory state in the periphery through several mechanisms. Timmerman et al. showed that exercise intervention (leg press and chest press) in aged participants (mean age 71 ± 5.7 years) can lower the quantity of

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circulating cluster of differentiation (CD)14+/CD16+ pro-inflammatory monocytes almost three fold (Timmerman et al., 2008). Others demonstrated that introduction of regular exercise (treadmill and resistance training) can reduce the levels of bacterial lipopolysaccharide (LPS)-stimulated secretion of pro-inflammatory cytokines. Tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β levels were decreased in whole blood samples from both young (mean age 25 ± 5 years) and old (mean age 71 ± 4.4 years) healthy individuals (Stewart et al., 2005). Previous research has demonstrated that adding exercise to one’s weekly routine reduces serum concentrations of the circulating pro-inflammatory cytokines TNF-α, a secreted signaling protein involved in inflammation and apoptosis, and IL-1β, an inflammatory mediator best known for its pyrogenic and immunomodulatory properties. Exercise has also been shown to reduce Creactive protein (CRP), a major biomarker of inflammation and predictor for a multitude of inflammatory diseases (Gleeson et al., 2011; McFarlin et al., 2006; Michigan et al., 2011). In conjunction with the reduction in pro-inflammatory mediators, exercise also increases circulating levels of the anti-inflammatory cytokine IL-1 receptor antagonist (IL-1ra) (Gleeson et al., 2011; McFarlin et al., 2006; Starkie et al., 2003; Steensberg et al., 2003). Furthermore, exercise appears to reduce the number of macrophages infiltrating adipose tissue in obese rodents (Kawanishi et al., 2013; Kawanishi et al., 2010), which is a major contributor to chronic systemic inflammation (Weisberg et al., 2003). Both rodent and human studies revealed that the introduction of an exercise regimen changes the phenotypes of resident adipose tissue macrophages from pro-inflammatory (M1) to anti-inflammatory (M2) (Bruun et al., 2006; Kawanishi et al., 2010). One theory explaining the mechanisms underlying the anti-inflammatory nature of PA states that the release of IL-6 from contracting skeletal muscle following each acute bout of exercise is responsible for the beneficial effects. It is proposed that the exercise-induced surge of IL-6 triggers the observed peripheral anti-inflammatory effects (Keller et al., 2003). Exercise also prompts the spleen to release T regulatory cells with an anti-inflammatory phenotype. These T regulatory cells have downregulated cellsurface expression of the major histocompatibility complex (MHC) II, an antigenpresenting molecule involved in triggering the adaptive immune response, and intercellular adhesion molecule 1 (ICAM1), which aids in extravasation of immune cells

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to sites of inflammation (Maynard and Weaver, 2008). Another novel theory argues that the anti-inflammatory effect of exercise in the periphery may be due to a reduction in the expression of toll-like receptor (TLR) 4 on a variety of cell and tissue types including monocytes, muscle, adipose tissue and the liver (Gleeson et al., 2011; McFarlin et al., 2006; Robinson et al., 2015). TLR4 is a receptor known for mediating innate immune cell activation, primarily in response to LPS. Up to a 50% reduction in TLR4 expression could be observed on CD14+ cells following exercise (Flynn and McFarlin, 2006; Stewart et al., 2005). Although the mechanism by which TLR4 is downregulated following exercise remains unclear, this may be due to the cross-tolerance of TLR4 to other secreted proteins, such as heat shock proteins (HSPs), which bind this receptor and are upregulated during bouts of exercise (Flynn and McFarlin, 2006; Kilmartin and Reen, 2004). This overall reduction in TLR4 due to cross-tolerance may account for some of the observed reduction in immune cell activation following exercise. The reduced immune cell activation following exercise and PA may also be explained by a decrease in the release of DAMPs by muscle cells, neutrophils, lymphocytes and endothelial cells (Giallauria et al., 2014; Shockett et al., 2016). Since DAMPs are known to elicit an inflammatory response, reduction in their concentration could lead to reduced immune cell activation and cytokine secretion (Land, 2015). Even though the mechanisms are not completely defined, most of the research indicates that exercise induces a whole-body anti-inflammatory phenotype, which may prove helpful for the prevention and treatment of chronic inflammatory conditions. Although there is overwhelming evidence to support the idea that PA and exercise are anti-inflammatory, there are several notable exceptions to this generalization. One of the caveats to this theory has been titled the elite athlete paradox (Gleeson et al., 2012; Gleeson et al., 2011; Nieman et al., 1990). Essentially, the long and intense hours of exercise training endured by elite athletes makes them more susceptible to upper respiratory tract infections. It has been proposed that this increased incidence of infection in this subset of the athletic population is due to exercise-induced overproduction of IL10. This leads to immunosuppression, since IL-10 has been shown to suppress pathogeninduced immune responses by inhibiting T cell proliferation and cytokine responses (Blackburn and Wherry, 2007; Gleeson et al., 2012; van der Sluijs et al., 2004). Another

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caveat involves observations that intense prolonged and strenuous exercise, in many cases, is associated with increased markers of inflammation and cellular damage (Comassi et al., 2015). For example, La Gerche et al. found that intense endurance exercise (3 to 11 hours in duration) in trained subjects correlated with dramatic increases in serum IL-6, IL-8, IL-10 and TNF- α concentrations (La Gerche et al., 2015). Additionally, 25% of these participants had serum inflammatory and cardiac markers at the levels that met the criteria for exercise-induced myocardial dysfunction. However, extreme exercise is not considered the norm, and it has even been classified as physiological stress (Neubauer et al., 2013).

Although certain regimens of intense

training provide some well-known health benefits to the individual, examples of potential drawbacks to the exhaustive exercise performed by elite athletes are equally well documented. Therefore, the benefits of exercise may depend on its intensity and duration in a bell-shaped fashion, where too little or too much exercise do not produce the benefits known to be associated with moderate exercise. 2.1 Physical activity and exercise as an intervention for peripheral diseases Many diseases associated with peripheral tissue damage or malfunction have an element of chronic systemic inflammation, which perpetuates the disease pathology. For example, T2DM is a disease characterized by chronic hyperglycemia owing to the reduced sensitivity of cells to insulin. The continuous dysregulation of plasma glucose levels generates an environment of chronic inflammation through means of increased levels of circulating pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) and advanced glycation end products (AGEs), as well as oxidative stress (Brundage et al., 2008; Iida et al., 2001; Nowotny et al., 2015). In addition to increasing muscle sensitivity to insulin (Holloszy, 2005), PA also reduces the pro-inflammatory environment in T2DM patients, as demonstrated by a reduction in the cellular markers of inflammation ICAM1 and CRP (Falconer et al., 2014; Zoppini et al., 2006). Since T2DM is considered a lifestyle-related disease, it is not surprising that diet and exercise are among the top preventative measures for this condition (McCarthy, 2015), and the preferred intervention above standard pharmacological treatments (Gaesser, 2007).

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The inflammation-reducing benefits of exercise are not limited to T2DM, however. PA has been shown to attenuate disease-associated inflammation and reduce recovery time following traumatic spinal cord injury. Some convincing examples include the use of arm exercises for the treatment of patients with chronic spinal cord injury. These patients showed significantly lower levels of CRP, IL-6 and TNF-α compared to their sedentary counterparts (Neefkes-Zonneveld et al., 2015; Rosety-Rodriguez et al., 2014). It has been known for some time that exercise reduces recovery time in patients following myocardial infarction, and recent research highlights that the root cause of this phenomenon may be the reduction of systemic inflammation In rodent studies, voluntary wheel running (VWR) has been used as a form of PA, while forced treadmill could be representative of human exercise (Garland et al., 2011; Kemi et al., 2002; Knab et al., 2009). Puhl et al. demonstrate that mice without access to means of additional PA, which experience a myocardial infarction, had elevated levels of circulating IL-6, TNF-α and IL-1β (up to 10 fold), increased infarct size and longer recovery time when compared to their physically active counterparts (Puhl et al., 2015). For a comprehensive review of how exercise improves inflammatory markers in individuals suffering from chronic inflammatory conditions in the periphery, see Ploeger et al. (Ploeger et al., 2009). 3. Physical activity and exercise and the brain The health benefits of exercise are not restricted to peripheral tissues, but extend to the CNS, as well. Several studies and supporting meta-analyses have demonstrated that exercise enhances mood in a wide demographic ranging from youth to seniors, and in healthy and diseased individuals alike (Adamson et al., 2015; Annesi and Tennant, 2012; Hoffman et al., 2010; Johnson and Castle, 2015; Powers et al., 2015). This is consistent with previous research, which has shown PA to enhance the neuronal release of serotonin (5-hydroxytryptamine, 5-HT) and dopamine (DA) (Melancon et al., 2014; MonteiroJunior et al., 2015), the so-called ‘happy’ neurotransmitters, since the binding of 5-HT and DA to their receptors brings on a feeling of euphoria (Dayan and Huys, 2008; Wise and Bozarth, 1985). Exercise is also beneficial to the brain because it is associated with enhanced long-term potentiation (LTP) and neurogenesis (Yu et al., 2013), as well as higher

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expression of brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF) and glial cell line derived neurotrophic factor (GDNF) (Gyorkos et al., 2014; Uysal et al., 2015).

Since exercise enhances the expression of growth and

neurotrophic factors, which are critical for learning and memory, it is not surprising that even a single bout of exercise can lead to improvements in these CNS functions (Weinberg et al., 2014). Piao et al. showed that following traumatic brain injury, long-term exercise can improve cognitive function in rodents measured by the Morris water maze (MWM) test up to 2.3 fold above their low activity counterparts (Piao et al., 2013). It is interesting to note that these cognitive improvements correlated with a decrease in levels of the proinflammatory cytokine IL-1β and an increase in the anti-inflammatory cytokine IL-10 in the brains of the exercised mice. This evidence shows that the benefits of PA in the CNS may not only be due to effects on neurons but also due to effects on the immune cells of the brain, the glial cells.

4. Neuroimmune-modifying effects of physical activity and exercise Inflammation in the CNS involves the recruitment and activation of specialized immune cells called glia. These include microglia, the resident macrophages of the CNS that specialize in debris clearance and antigen presentation; astrocytes, which specialize in neuronal support and tissue repair; and oligodendrocyes, which insulate and support neurons (Jessen, 2004). In the presence of infection or injury, glia become activated and work together to repair the damage and restore brain homeostasis (Frank-Cannon et al., 2009; Lull and Block, 2010).

Upon activation, microglia undergo a morphological

transformation from a resting (ramified) phenotype to a phagocytic (amoeboid) phenotype. Microglia can become activated to either an M1 or an M2 phenotype, similar to the phenotypes observed in peripheral macrophages. These two polarization states of microglia have been shown to coexist in the brains of AD mouse models (Colton et al., 2006; Varnum and Ikezu, 2012). Activated Microglia increase expression of their cell membrane receptors, including MHC II and macrophage antigen complex (MAC)-1 (Lull and Block, 2010), and also undergo secretome changes including increased release of inflammatory mediators, such as cytokines (e.g., IL-6, IL-1β and TNF-α), and reactive 10

oxygen species (ROS) (Block et al., 2007). Microglia can also increase the secretion of neurotrophic factors, such as BDNF, neurotrophin (NT)-3 and NT-4, which serve as neuronal survival signals that aid in re-establishing homeostasis in the brain (Block and Hong, 2005; Block et al., 2007). However, in some diseases, such as AD and PD, glial cells become adversely activated by the persistent presence of pathological formations, resulting in a chronic neuroinflammatory environment (Block and Hong, 2005). Such over activation of glial cells (termed gliosis or reactive gliosis) and chronic inflammation has been classified as a detrimental process due to the non-specific nature of the innate immune system. These responses have been shown to induce collateral damage to other surrounding glial cells and neurons, thus perpetuating the disease progression (Minghetti et al., 2005). New evidence has emerged suggesting that, in addition to having inflammationmodifying properties in the periphery, exercise can modify inflammation in the CNS. Research shows that the aged brain is typically characterized by enhanced sensitivity to glial cell stimulation, often referred to as glial priming (Dilger and Johnson, 2008). Microglia that have been primed, either due to the aging process, or due to priming stimuli, such as interferon (IFN)-γ, have enhanced expression of receptors that respond to subsequent deleterious stimuli. Some of the upregulated receptors include CD14, CD45, MAC-1, MHC II and TLR4 (Dilger and Johnson, 2008; Lull and Block, 2010; Parajuli et al., 2012).

Primed microglia are better adept at providing a rapid and appropriate

response to endogenous stimuli as well as pathogenic invaders (Dilger and Johnson, 2008). However, in the presence of chronic pathological stimuli, primed immune cells can become over activated leading to further deleterious effects (Cunningham, 2013). A recent study showed that VWR in aged mice reduced microglia proliferation approximately 1.5 fold and decreased the number of M1 activated microglia approximately 1.8 fold.

These findings suggest that PA induces an anti-

neuroinflammatory phenotype similar to the effects of PA on the peripheral immune system (Kohman et al., 2012).

Researchers were also able to demonstrate certain

neuroprotective effects of VWR in younger mice, such as a reduction in trimethyltininduced neurotoxicity in the hippocampus (Funk et al., 2011).

This reduction in

neurotoxicity may be attributed to altered inflammation in the CNS, as demonstrated by

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an approximately two-fold reduction in the CNS concentrations of IL-6, monocyte chemotactic protein (MCP)-1 and TNF-α. However, not all research supports the idea that exercise leads to strictly anti-inflammatory effects in the brain. Packer and HoffmanGoetz found that acute exercise (treadmill running) in mice resulted in increased hippocampal levels of TNF-α, and increased apoptosis, as measured by elevated levels of caspase-3 and caspase-7 (Packer and Hoffman-Goetz, 2015). These data support the idea that the overall effect of exercise could vary depending on its intensity. Other experts in this field of research have proposed that exercise may condition immune cells of the CNS for an appropriate immune response when compared to the stagnant CNS immune system of individuals who do not exercise regularly (Smith et al., 1996). Here we discuss evidence supporting the use of PA and exercise as a therapeutic intervention and neuroinflammation modifying tool in the affective diseases MDD and SCH, as well as the neurodegenerative disorders AD and PD. 4.1 Anti-inflammatory effects of physical activity and exercise in major depressive disorder MDD is classified as an affective disorder, characterized by one or more depressive episodes due to physiological changes in brain structure and function (Uher et al., 2014). The symptoms of MDD are quite recognizable and include sad mood, changes in sleep patterns, changes in weight (not related to diet and exercise), fatigue, inability to concentrate and/or suicidal thoughts, which are present every day for at least two weeks (Pies, 2009). Several hypotheses attempt to explain the pathogenesis of MDD. They include the monoamine hypothesis, which proposes that MDD is caused by a functional deficit of monoamine neurotransmitters, mainly 5-HT (Nutt, 2002; Tissot, 1975); the neurotransmitter receptor hypothesis, which states that MDD is a result of abnormalities in monoamine transmitter receptors in the CNS (Bennett, 2010; Stahl, 1984); the novel neuroplasticity hypothesis, which hinges on the evidence that MDD sufferers have abnormal glutamate (Glu) signaling in their brains (Sanacora et al., 2012; Xu, 2008); and the inflammatory hypothesis, which proposes that MDD is a cytokine-mediated disorder (Maes, 1995; Raedler, 2011).

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The latter hypothesis places the role of glia cells and the associated presence of chronic neuroinflammation at the center of MDD pathogenesis. Post-mortem studies showed that patients with mood disorders consistently displayed a significant decrease in glia density (up to 40% reduction) in the prefrontal cortex and limbic centers of the brain (Altshuler et al., 2010; Cotter et al., 2001; Rajkowska et al., 1999), as well as fewer astrocytes guarding the CNS at the blood brain barrier (BBB) (Rajkowska et al., 2013). Despite the decrease in their numbers, glial cells in the cortex and hippocampus were over activated, which was further exacerbated in the brains of depressed individuals who died by suicide (Torres-Platas et al., 2014). Clinical data showed that levels of the peripheral and CNS pro-inflammatory markers CRP, TNF-α, and IL-6, are significantly increased in MDD patients compared to healthy controls (Dowlati et al., 2010; Valkanova et al., 2013). Furthermore, depression has high comorbidity rates with immune- and autoimmune-associated diseases including inflammatory bowel disease, T2DM and psoriasis, to name a few (Maes et al., 2011). It is well documented that PA produces beneficial effects in individuals with MDD. Exercise enhances mood in the young, the old, the sick and the healthy alike (Annesi and Tennant, 2012; Hoffman et al., 2010; Johnson and Castle, 2015; Powers et al., 2015). This elevation in mood following exercise has been attributed primarily to the enhanced release of the neurotransmitters 5-HT and DA by neurons (Melancon et al., 2014; Monteiro-Junior et al., 2015). However, the MDD symptom-reducing effects of exercise may not only be due to an increase of 5-HT and DA in the CNS, but also due to a reduction in MDD-associated neuroinflammation (Eyre and Baune, 2012; Liu et al., 2013). A study by Liu et al. showed that mice with stress-induced depression had completely abolished depressive behavior following long-term swimming exercise intervention (Liu et al., 2013). This reduction in the severity of depression was correlated with an increase in 5-HT and a decrease in the pro-inflammatory cytokines IFN-γ and TNF-α (~30% reduction for each) in the prefrontal cortex. A recent study by Agudelo et al. revealed that enhancement of the skeletal muscle peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α1 by exercise training protected mice from stressinduced depression in an inflammation-dependent manner (Agudelo et al., 2014). Exercise training significantly increased skeletal muscle expression of PGC-1α1, which

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upregulates kynurenine aminotransferases (KATs). Kynurenine, an endogenous agonist of Glu receptors, which is strongly associated with MDD via modulation of neuronal death and inflammation (Dantzer et al., 2011), is converted by KATs to kynurenic acid, a compound that cannot cross the BBB (Olah et al., 2013). It has been proposed that enhanced expression of PGC-1α1 following exercise significantly reduces depressive behaviors and hippocampal expression of MCP-1, TNF-α, IL-1β and IL-6, in a kynurenine pathway-dependent manner (Adamson et al., 2015). However, not all mouse studies support the conclusion that exercise improves markers of neuroinflammation in MDD. Martin et al. demonstrated that VWR had no effect on LPS-induced sickness behaviors, including loss of appetite, decrease in body weight, fatigue, reduced social behavior, and altered cognition, in young and old mice alike. In this study VWR also failed to reduce LPS-induced increases in TNF-α, IL-1β and IL-6 in mice brains (Martin et al., 2014). An exercise intervention study in humans found that the exercise-induced improvements in the symptoms of depression correlated with a significant decline in serum concentration of IL-1β (Rethorst et al., 2013). This could perhaps be interpreted to mean that circulating IL-1β may be used as a potential biomarker for MDD, while a decline in IL-1β could mark improvements in MDD. Several other clinical studies have demonstrated that exercise is highly effective at reducing the clinical symptoms and minimizing the rate of reoccurrence of MDD episodes (Blumenthal et al., 2007; Doose et al., 2015; Dunn et al., 2005). The general consensus among experts remains that more frequent activity over a longer period of time, results in greater efficacy of exercise in the treatment of MDD (Carek et al., 2011), which is likely due, at least in part, to the inflammation-altering effects of exercise. 4.2 Anti-inflammatory effects of physical activity and exercise in schizophrenia PA has also been shown to have beneficial effects in SCH, which is another affective disorder.

Although the root causes of this mental disorder are not well

understood, the symptoms are well characterized and include hallucinations, delusions, paranoid thoughts and ideas, as well as mood disorder symptoms (Arciniegas, 2015). There are many elements that contribute to the onset of SCH including genetic,

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environmental, molecular and physiological factors. The most popular theories behind the causes of SCH are the dopaminergic and the glutamatergic hypotheses. The longstanding dopaminergic hypothesis attributes the psychosis-related symptoms of SCH to overactive DA signaling, primarily in the cortex (Howes and Kapur, 2009). This theory is supported by evidence showing that effective antipsychotic drugs increase the metabolism of DA when given to animals (Carlsson and Lindqvist, 1963). Similarly, a 10 - 20% increase in D2 and D3 DA receptor distribution has been shown in the cortex of individuals with SCH (Kestler et al., 2001). In contrast, the more modern glutamatergic hypothesis states that SCH is a result of reduced Glu signaling in the brain (Kornhuber et al., 1984). These two theories are highly related, since DA inhibits the release of Glu. Therefore, an overactive dopaminergic system would inhibit Glu signaling in the schizophrenic brain, which could lead to manifestations of psychosis (Javitt, 2007). In addition to these two theories, there is mounting evidence for the role of dysregulated neuroinflammation and oxidative stress in the progression of SCH (Leza et al., 2015), as well as the role of microglia activation in the neuropathology of SCH (Kanba and Kato, 2014). A significant increase in glial activation has been observed in the prefrontal cortex of patients with SCH as demonstrated by increased expression of MHC II, a marker of microglial activation; CD44, an antigen associated with immune cell adhesion and migration; and ICAM1, which primarily functions to facilitate translocation of immune cells across the endothelial layer of the BBB (Fillman et al., 2013). When examining the frontal cortex of post-mortem SCH patients, Rao et al. found a significant elevation in activation markers of microglia (MAC-1) and astrocytes (glial fibrillary acidic protein [GFAP]), compared to brains of age-matched healthy controls (Rao et al., 2013). These patients also exhibited an increase in arachidonic acid (AA) signaling (a major contributor to inflammation) as evident by an increase in phospholipase A2 and cyclooxygenase (COX)-2 (approximate 50% increase).

This significant increase in

gliosis and AA signaling was accompanied by a two-fold increase in brain IL-1β levels, a 1.5-fold increase in TNF-α levels, and a 1.5-fold increase in nuclear factor kappa B (NFκB), the upstream transcription factor for these cytokines. In fact, SCH could be associated with a specific profile of serum cytokines and chemokines, which has been

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used to set up a new biomarker panel for the diagnosis of SCH, with almost 90% accuracy (Noto et al., 2015). With the desperate need for more effective treatment options for SCH, several researchers have shifted their focus on the therapeutic potential of exercise in SCH instead of solely relying on the standard pharmacotherapeutic options. Studies have demonstrated the efficacy of aerobic exercise in treating the cognitive and biochemical deficits found in SCH patients (Archer and Kostrzewa, 2015). In addition to enhanced expression of insulin-like growth factor (IGF)-1 and BDNF (Kim et al., 2014; Kuo et al., 2013), people suffering from SCH who led an active lifestyle had lower levels of serum CRP when compared to the sedentary control population (Stubbs et al., 2015). It has been proposed that the overproduction of pro-inflammatory cytokines inhibits the release of BDNF (Calabrese et al., 2014), since intraperitoneal injection of IL-1β resulted in a reduction in BDNF gene expression in the hippocampus of rodents (Lapchak et al., 1993). Furthermore, systemic inflammation in rodents has been shown to reduce not only BDNF, but also other hippocampal NTs including nerve growth factor (NGF) and NT-3 (Guan and Fang, 2006). Although this link has yet to be explicitly investigated, the observed increase in cognitive abilities and neurotrophic factors displayed in SCH patients following exercise may be a result of PA-induced reduction of peripheral or brain inflammatory cytokines. 4.3 Anti-inflammatory effects of physical activity and exercise in Alzheimer’s disease In contrast to the affective disorders, AD is an age-related neurodegenerative disease. This disease is characterized by a decline in memory and cognitive ability caused by the deposition of amyloid beta (Aβ) and the formation of neurofibrillary tangles (NFTs), leading to neuronal death (Hauw et al., 1990; Mandybur, 1989). These pathological formations trigger the activation of glial cells. Once activated, glia alter their secretory profile in aims of degrading and eliminating the Aβ plaques and NFTs, but with little success. This leads to a cyclical process of chronically activated microglia and neuronal death, termed reactive gliosis. Mouse models of AD and clinical data from AD patients show significant activation of astrocytes and microglia in the frontal cortex and hippocampus, the brain regions with highest concentrations of Aβ plaques and NFTs

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(Kamphuis et al., 2012; Mandybur, 1989; Mori et al., 2010; Rao et al., 2011; SerranoPozo et al., 2011). Since reactive gliosis is observed in AD brains, it is not surprising that it is accompanied by a significant upregulation of pro-inflammatory cytokines, chemokines and inflammatory enzymes compared to non-diseased controls. More specifically, the post-mortem brains of AD patients have an approximately two-fold increase in COX-2 gene expression, a slight but significant increase in COX-1, as well as an increase in 12lipoxygenase (LOX) (two fold) and 15-LOX (1.5 fold). These, in turn, could lead to the production of such potent inflammatory mediators as prostaglandins, prostacyclins, thromboxanes, and leukotrienes (Harizi et al., 2008). This upregulation is accompanied by a three-fold increase in CNS IL-1β and a 2.5-fold increase in TNF-α compared to control subjects (Rao et al., 2011). These results are supported by other clinical studies that have shown a 4- to 7-fold increase in IL-6, IL-8 and MCP-1 in the brains of AD patients compared to non-demented controls (Sokolova et al., 2009). Studies have shown that VWR enhances learning and memory in aged mice, as evaluated by the MWM test. The demonstrated improvements in learning and memory correlated with a 2-fold increase in neurogenesis in the hippocampus of PA mice (Gibbons et al., 2014). Several other studies presented similar results, demonstrating elevated brain concentrations of BDNF, VEGF and IGF-1, a decrease in ROS and increased learning and memory with the introduction of PA and exercise (Erickson et al., 2012; Eyre and Baune, 2012; Radak et al., 2007; Radak et al., 2013; Suijo et al., 2013; Yu et al., 2014). PA and exercise have also been shown to improve memory in mouse models of AD, and it has been suggested that this improvement may be attributed to the PA-induced decline in neuroinflammation (Kang et al., 2013; Tapia-Rojas et al., 2016; Zhao et al., 2015). Kang et al. showed that the transgenic presenilin 2 mutant AD model mice that participated in exercise had significantly less Aβ deposition in the cortex and hippocampus compared to their less physically active counterparts (Kang et al., 2013). This decline in pathological formations in the exercise group was correlated with a decline in markers of apoptosis (cleaved caspase-12, and cleaved caspse-3), and a significant reduction in TNF-α and IL-1α. In fact, the exercised rodent models of AD improved to the point that they more closely resembled the controls than the less active

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AD group. Other AD rodent studies (using NSE/htau23 mice) have shown a 2.7-fold reduction in the number of activated microglia (indicated by staining with anti-Iba-1 antibodies) and a nine-fold reduction in the number of activated astrocytes (shown by GFAP expression) upon introduction of exercise (Leem et al., 2011). In addition to a reduction in the number of activated glial cells, these mice showed a decline in COX-2, inducible nitric oxide synthase (iNOS), TNF-α, IL-1β and IL-6 (approximately 2 fold each). Other researchers found similar results using alternative mouse models of AD (Belarbi et al., 2011; Nichol et al., 2008). To date, most studies of the immune-modifying effect of PA in the CNS have been performed in mice. However, novel research with human subjects has demonstrated that PA can reduce the probability of developing neurodegenerative diseases. Several randomized controlled clinical trials revealed that exercise slowed the progression of cognitive decline from mild cognitive impairment to AD. Moreover, the exercise group displayed significantly greater memory, cognitive and executive function when compared to the inactive/sedentary group (de Andrade et al., 2013; Law et al., 2014). Although human studies have yet to confirm that exercise reduces AD symptoms through inflammatory mechanisms, animal studies and human studies involving non-demented individuals suggest attenuating inflammation may be one of the mechanisms by which PA and exercise improve the pathophysiology and symptoms associated with AD (Belarbi et al., 2011; de Andrade et al., 2013; Fiuza-Luces et al., 2013; Kang et al., 2013; Law et al., 2014; Tapia-Rojas et al., 2016). Moreover, it has been estimated that leading a physically active lifestyle reduces the risk of developing AD by up to 2.7 fold (Barnes and Yaffe, 2011; Scarmeas et al., 2009). In addition to showing promising results in preventing onset and alleviating the progression of AD, PA has also been shown to be a valid intervention strategy in other neurodegenerative diseases including PD. 4.4 Anti-inflammatory effects of physical activity and exercise in Parkinson’s disease PD, an age-related neurodegenerative disease, is characterized predominantly by physical, rather than cognitive manifestations. Some of the symptoms of PD include rigid, slow movement of voluntary muscles (bradykinesia) accompanied by resting

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tremor and postural instability (Mahlknecht and Poewe, 2013; Santiago and Potashkin, 2013). These physical manifestations are a result of the aggregation of -synuclein protein, which forms insoluble Lewy bodies, and of the selective loss of dopaminergic neurons. These changes take place primarily in the substantia nigra pars compacta region of the brain, which is responsible for coordinating finite movements (Mahlknecht and Poewe, 2013; Marques and Outeiro, 2012; Morris et al., 2011).

The -synuclein

aggregates and necrotic neurons activate microglia, which then secrete cytokines, chemokines and ROS in aims of degrading these pathological fragments (Qin et al., 2013; Zhang et al., 2005).

Similar to the pathology of AD, these formations cannot be

destroyed by microglia and thus, the brains of PD patients are in a chronic state of reactive gliosis, resulting in greater neuronal damage (Czlonkowska et al., 2002; Qian et al., 2010; Teismann et al., 2003).

Post-mortem PD brains have shown significant

microglia and astrocyte activation and increased levels of IL-1β, IL-2, IL-4, IL-6, TNF-α, TNF receptor 1, as well as increased activation of NFκB (Banati et al., 1998; Nagatsu et al., 2000; Reynolds et al., 2008). The increased presence of TNF-α and TNF receptors plays a critical role in the pathology of PD, as TNF-α triggers the initiation of extrinsic neuronal apoptosis, one of the major factors implicated in the pathology of PD (Ruberg et al., 1997). Furthermore, novel anti-inflammatory drugs designed to minimize microglial activation and neuroinflammation, as well as common non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, have shown promising neuroprotective effects when administered in the early stages of PD (Ouchi et al., 2009; Rees et al., 2011). In addition to conventional pharmaceutical methods, the immune-modifying role of PA has become of great interest as a potential therapeutic intervention in PD (Bloem et al., 2015). Several studies have demonstrated that regular aerobic exercise improves balance and motor symptoms, reduces indicators of depression, improves cardiovascular health, and enhances overall quality of life in PD patients in short-term and long-term follow up studies alike (Canning et al., 2015; Frazzitta et al., 2015; Frazzitta et al., 2014; Uc et al., 2014).

Two studies showed that these improvements in PD symptoms

correlated with a normalization in the level of circulating biomarkers of PD. Frazzitta et al. showed a 16% increase in serum BDNF in PD patients following intense exercise intervention, which correlated with a 32 - 41% improvement in the Unified Parkinson’s

19

Disease Rating Scale (UPDRS), a score used to estimate the severity of PD and detect benefits of therapeutic interventions (Frazzitta et al., 2014). A separate study found that moderate-intensity interval training increased serum BDNF by 80%, reduced serum vascular cell adhesion molecule (VCAM) by 25%, and reduced serum TNF-α by 9% in PD patients (Zoladz et al., 2014).

Animal studies confirmed these findings by

demonstrating that exercise intervention in rodent models of PD improved overall motor skills, along with an increase in BDNF, GDNF, and higher concentrations of DA in the substantia nigra and striatum compared to the low activity PD counterparts (Lau et al., 2011). This is not surprising, however, since PA stimulates the synthesis of DA and trophic factors, which promote neuroplasticity and inhibit apoptosis and inflammation, thereby delaying the progression of PD symptoms (Monteiro-Junior et al., 2015). In addition, epidemiological studies report that leading an active lifestyle reduces the risk of developing PD by approximately two fold (Zou et al., 2015). 5. Summary and hypotheses Experimental and epidemiological studies have demonstrated that living a healthy and physically active lifestyle reduces the risk (Barnes and Yaffe, 2011; Scarmeas et al., 2009; Zou et al., 2015) and severity of neurological diseases (Archer and Kostrzewa, 2015; Canning et al., 2015; Erickson et al., 2012; Eyre and Baune, 2012; Frazzitta et al., 2015; Frazzitta et al., 2014; Liu et al., 2013; Radak et al., 2007; Radak et al., 2013; Suijo et al., 2013; Uc et al., 2014; Yu et al., 2014). However, the cellular and molecular mechanisms responsible for these beneficial effects of PA have not been established. This article highlights the available evidence suggesting that PA and exercise can modulate brain disease through neuroimmune mechanisms. One of the long-standing theories proposes that PA and exercise regulate immune functions through enhanced myokine (muscle derived cytokines and peptide hormones) secretion. Some of the well-defined myokines include, IL-4, myostatin, BDNF and most notably IL-6 (Stranska and Svacina, 2015). During and following exercise, a large and transient amount of IL-6 is excreted from contracting myocytes (Rohde et al., 1997) inducing a wide range of anti-inflammatory responses in the periphery (Gleeson et al., 2011; Kawanishi et al., 2010; Prestes et al., 2008; Selkirk et al., 2009). However, IL-6 is

20

also known to cross the BBB (Banks et al., 1995), thus providing a direct line of communication between contracting muscles and the CNS immune system. IL-6 is a dual-function cytokine, which depending on the circumstances, could have either neurotoxic or neuroprotective activity in the CNS (Brett et al., 1995; Fattori et al., 1995; Maeda et al., 1994; Swartz et al., 2001). Evidence suggests that IL-6 acts in an antiinflammatory manner in the CNS following exercise.

For example, IL-6 enhances

expression of metallothionein (Giralt et al., 2002), a Golgi apparatus protein with strong anti-inflammatory, anti-oxidative, and anti-apoptotic properties (Penkowa et al., 2003). Therefore, IL-6 production following exercise could lead to attenuation of neuronal death, neuroinflammation and brain ROS production in a metallothionein-dependent manner. Moreover, IL-10 is produced by macrophages and T regulatory cells in response to skeletal muscle secretion of IL-6 and acts as an anti-inflammatory molecule by inhibiting the peripheral production of IL-1α, IL-1β, and TNF-α (Gleeson et al., 2011). Since each of these cytokines is capable of crossing the BBB (Banks et al., 1995), upregulation of IL-6 following exercise reduces systemic and CNS levels of pro-inflammatory cytokines, which represents one of the mechanisms by which exercise reduces the chronic neuroinflammation observed in SCH, MDD, AD and PD (Fig. 1). Exercise also decreases the number of macrophages infiltrating adipose tissue (Kawanishi et al., 2013; Kawanishi et al., 2010), thus inhibiting a critical mechanism of chronic systemic inflammation (Weisberg et al., 2003). Furthermore, both rodent and human studies have demonstrated that exercise can change the phenotype of resident adipose tissue macrophages from an M1 to M2 type (Bruun et al., 2006; Kawanishi et al., 2010). This switch in macrophage phenotype is accompanied by a shift in their cytokine secretion profile from pro-inflammatory (TNF-α secretion) to anti-inflammatory (IL-10 and adiponectin secretion) (Gleeson et al., 2011), which may have a direct impact on cytokine levels and immune responses in the CNS (Fig. 1) (Banks et al., 1995). Alternatively, the neuroimmune benefits of exercise could be due to modulation of the kynurenine pathway. Although the effects of kynurenine, a neurotoxic Glu agonist, have been studied extensively in MDD, additional research has demonstrated that an imbalance of the kynurenine pathway is also common to SCH, AD and PD (Gong et al., 2011; Kegel et al., 2014; Zinger et al., 2011). Therefore it is reasonable to hypothesize

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that following PA enhanced skeletal muscle-mediated conversion of the neurotoxin kynurenine, which is capable of crossing the BBB, to kynurenic acid, a compound which does not readily cross the BBB (Olah et al., 2013), could be beneficial in regulating diseases other than MDD. Deficit of kynurenine in the CNS could reduce neuronal death and inflammation in SCH, AD and PD (Adamson et al., 2015; Agudelo et al., 2014), and may be one of the beneficial immune system-mediated effects of exercise in CNS diseases (Fig. 1). A great deal of research has shown that brain immune cells become primed or activated with age (Lynch et al., 2010; Rozovsky et al., 1998) and in individuals with neurological diseases (Cameron and Landreth, 2010; Dheen et al., 2007; Reynolds et al., 2008). It has been demonstrated that exercise reduces microglia activation in aged mice (Kohman et al., 2012), as well as minimizes activation of both astrocytes and microglia in mouse models of AD (Leem et al., 2011; Nichol et al., 2008). Therefore, it is possible that regular/moderate exercise maintains the activation of glia within a healthy range, which may be contributing to the reduced incidence of brain disease in individuals who exercise regularly. 6. Conclusion Although it has been accepted for years that PA is necessary to maintain a healthy body and mind, the true scope of the benefits of PA and exercise at the cellular and molecular level has yet to emerge. Recent evidence highlights the potential for PA and exercise to reduce peripheral and CNS diseases that have an underlying element of chronic inflammation. This is particularly relevant for brain diseases such as MDD, SCH, AD and PD, which involve mechanisms that are still poorly understood, resulting in a lack of effective treatment options. For example, MDD is a lifetime illness for many since effective long-term anti-depressant medications are not available. Introduction of exercise could be a viable long-term option for most patients (Blier et al., 2007; Powers et al., 2015). Since exercise has been shown to slow memory decline, improve cognition, and enhance mood (de Andrade et al., 2013; Law et al., 2014; Osborn and Saunders, 2010), educating patients about the benefits of exercise would also represent a novel therapeutic strategy for AD.

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Overall, studies on the effect of PA and exercise on disease progression in MDD, SCH, AD and PD have shown that being physically active protects the brain by elevating the expression of neurotrophic factors, enhancing the release of neurotransmitters and increasing neurogenesis. Attenuation of glial cell activation and the resulting reduction of inflammation is an additional benefit of PA and exercise, since each of these diseases is characterized by a state of chronic neuroinflammation. The neuroimmune-modifying effects of PA may be the key underlying mechanism that helps prevent and alleviate these diseases. However, our current understanding of the overall neuroimmune-modifying effects of exercise and PA are limited.

Identifying the direct and indirect root

mechanisms that lead to the neuroimmune effects of exercise may identify new therapeutic targets to help slow down the progression of these particular diseases. Further studies optimizing the human exercise regimens to maximize their beneficial effects on neuroimmune status in these diseases are also required. Acknowledgements AK is supported by grants from the Jack Brown and Family Alzheimer’s Disease Research Foundation, the Natural Science and Engineering Research Council of Canada and the University of British Columbia Okanagan Campus.

JPL is supported by a

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