Cognitive and Behavioral Consequences of Impaired Immunoregulation in Aging

Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA.
Journal of Neuroimmune Pharmacology (Impact Factor: 4.11). 09/2011; 7(1):7-23. DOI: 10.1007/s11481-011-9313-4
Source: PubMed


A hallmark of the aged immune system is impaired immunoregulation of the innate and adaptive immune system in the periphery and also in the central nervous system (CNS). Impaired immunoregulation may predispose older individuals to an increased frequency of peripheral infections with concomitant cognitive and behavioral complications. Thus, normal aging is hypothesized to alter the highly coordinated interactions between the immune system and the brain. In support of this notion, mounting evidence in rodent models indicate that the increased inflammatory status of the brain is associated with increased reactivity of microglia, the innate immune cells of the CNS. Understanding how immunity is affected with age is important because CNS immune cells play an integral role in propagating inflammatory signals that are initiated in the periphery. Increased reactivity of microglia sets the stage for an exaggerated inflammatory cytokine response following activation of the peripheral innate immune system that is paralleled by prolonged sickness, depressive-like complications and cognitive impairment. Moreover, amplified neuroinflammation negatively affects several aspects of neural plasticity (e.g., neurogenesis, long-term potentiation, and dendritic morphology) that can contribute to the severity of neurological complications. The purpose of this review is to discuss several key peripheral and central immune changes that impair the coordinated response between the immune system and the brain and result in behavioral and cognitive deficits.

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Available from: Jonathan Godbout, May 15, 2015
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    • "In general, microglia activation and the increased expression of cytokines are aimed to be protective to the CNS and beneficial to the host organism. This is represented in their role in mediating the behavioral symptoms of sickness following innate immune challenge (Corona et al., 2012). Moreover, a recent study shows that repeated injection of lipopolysaccharide (LPS) moves microglia towards a novel profile in which they migrate to the synapses of inhibitory neurons displacing them from cortical neurons (Chen et al., 2014). "
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    ABSTRACT: Glia of the central nervous system (CNS) help to maintain homeostasis in the brain and support efficient neuronal function. Microglia are innate immune cells of the brain that mediate responses to pathogens and injury. They have key roles in phagocytic clearing, surveying the local microenvironment and propagating inflammatory signals. An interruption in homeostasis induces a cascade of conserved adaptive responses in glia. This response involves biochemical, physiological and morphological changes and is associated with the production of cytokines and secondary mediators that influence synaptic plasticity, cognition and behavior. This reorganization of host priorities represents a beneficial response that is normally adaptive but may become maladaptive when the profile of microglia is compromised. For instance, microglia can develop a primed or pro-inflammatory mRNA, protein and morphological profile with aging, traumatic brain injury and neurodegenerative disease. As a result, primed microglia exhibit an exaggerated inflammatory response to secondary and sub-threshold challenges. Consequences of exaggerated inflammatory responses by microglia include the development of cognitive deficits, impaired synaptic plasticity and accelerated neurodegeneration. Moreover, impairments in regulatory systems in these circumstances may make microglia more resistant to negative feedback and important functions of glia can become compromised and dysfunctional. Overall, the purpose of this review is to discuss key concepts of microglial priming and immune-reactivity in the context of aging, traumatic CNS injury and neurodegenerative disease. Copyright © 2014. Published by Elsevier Ltd.
    Neuropharmacology 11/2014; 96(Pt A). DOI:10.1016/j.neuropharm.2014.10.028 · 5.11 Impact Factor
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    • "types of microglia around Ab plaques contributes to cognitive decline in mouse models of AD . Cognitive decline indeed appears to result from brain inflammation which occurs with aging ( Villeda et al . , 2011 ; Weinstock et al . , 2011 ) or with peripheral inflammation , for example , upon intraperitoneal injection of lipopolysaccharide ( LPS ) ( Corona et al . , 2012 ; Cunningham , 2013 ) . Such inflammatory reactions indeed result in thicker and less branched and motile microglial processes which overall exhibit reduced coverage area ( Cunningham , 2013 ) ."
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    ABSTRACT: Microglia integrate within the neural tissue with a distinct ramified morphology through which they scan the surrounding neuronal network. Here, we used a digital tool for the quantitative morphometric characterization of fine cortical microglial structures in mice, and the changes they undergo with aging and in Alzheimer's-like disease. We show that, compared with microglia in young mice, microglia in old mice are less ramified and possess fewer branches and fine processes along with a slightly increased proinflammatory cytokine expression. A similar microglial pathology appeared 6–12 months earlier in mouse models of Alzheimer's disease (AD), along with a significant increase in brain parenchyma lacking coverage by microglial processes. We further demonstrate that microglia near amyloid plaques acquire unique activated phenotypes with impaired process complexity. We thus show that along with a chronic proinflammatory reaction in the brain, aging causes a significant reduction in the capacity of microglia to scan their environment. This type of pathology is markedly accelerated in mouse models of AD, resulting in a severe microglial process deficiency, and possibly contributing to enhanced cognitive decline.
    Aging cell 03/2014; 13(4). DOI:10.1111/acel.12210 · 6.34 Impact Factor
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    • "Similarly, elevations of proinflammatory cytokines (e.g., interleukin [IL]-1, IL-6, tumor necrosis factor [TNF]) and chemokines (e.g., RANTES [regulated upon activation , normal T-cell expressed, and secreted]) are evidenced in patients diagnosed with a range of chronic neuropsychiatric disorders including depression (Maes et al. 1995; Levine et al. 1999; Owen et al. 2001; Hestad et al. 2003; Loftis et al. 2008; Howren et al. 2009; Leonard and Maes 2012), anxiety (Hoge et al. 2009; Hou and Baldwin 2012), chronic fatigue syndrome (Arnett and Clark 2012), cancer-related fatigue and cognitive impairment (Meyers et al. 2005), pain disorders (Slade et al. 2011; Alexander et al. 2012), and age-related cognitive decline and dementia (Yaffe et al. 2004; Britschgi and Wyss-Coray 2009; Marksteiner et al. 2011; Corona et al. 2012). Collectively, these studies highlight the impact that immune activation and immune factor dysregulation (both peripherally and centrally) can have on central nervous system (CNS) function. "
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    ABSTRACT: The purpose of this study was to characterize hepatitis C virus (HCV)-associated differences in the expression of 47 inflammatory factors and to evaluate the potential role of peripheral immune activation in HCV-associated neuropsychiatric symptoms—depression, anxiety, fatigue, and pain. An additional objective was to evaluate the role of immune factor dysregulation in the expression of specific neuropsychiatric symptoms to identify biomarkers that may be relevant to the treatment of these neuropsychiatric symptoms in adults with or without HCV. Blood samples and neuropsychiatric symptom severity scales were collected from HCV-infected adults (HCV+, n = 39) and demographically similar noninfected controls (HCV−, n = 40). Multi-analyte profile analysis was used to evaluate plasma biomarkers. Compared with HCV− controls, HCV+ adults reported significantly (P < 0.050) greater depression, anxiety, fatigue, and pain, and they were more likely to present with an increased inflammatory profile as indicated by significantly higher plasma levels of 40% (19/47) of the factors assessed (21%, after correcting for multiple comparisons). Within the HCV+ group, but not within the HCV− group, an increased inflammatory profile (indicated by the number of immune factors > the LDC) significantly correlated with depression, anxiety, and pain. Within the total sample, neuropsychiatric symptom severity was significantly predicted by protein signatures consisting of 4–10 plasma immune factors; protein signatures significantly accounted for 19–40% of the variance in depression, anxiety, fatigue, and pain. Overall, the results demonstrate that altered expression of a network of plasma immune factors contributes to neuropsychiatric symptom severity. These findings offer new biomarkers to potentially facilitate pharmacotherapeutic development and to increase our understanding of the molecular pathways associated with neuropsychiatric symptoms in adults with or without HCV.
    Brain and Behavior 03/2014; 4(2):123-42. DOI:10.1002/brb3.200 · 2.24 Impact Factor
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