Microglial Activation and Chronic Neurodegeneration

Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Campus, Richmond, Virginia 23298, USA.
Journal of the American Society for Experimental NeuroTherapeutics (Impact Factor: 5.05). 10/2010; 7(4):354-65. DOI: 10.1016/j.nurt.2010.05.014
Source: PubMed


Microglia, the resident innate immune cells in the brain, have long been implicated in the pathology of neurodegenerative diseases. Accumulating evidence points to activated microglia as a chronic source of multiple neurotoxic factors, including tumor necrosis factor-α, nitric oxide, interleukin-1β, and reactive oxygen species (ROS), driving progressive neuron damage. Microglia can become chronically activated by either a single stimulus (e.g., lipopolysaccharide or neuron damage) or multiple stimuli exposures to result in cumulative neuronal loss with time. Although the mechanisms driving these phenomena are just beginning to be understood, reactive microgliosis (the microglial response to neuron damage) and ROS have been implicated as key mechanisms of chronic and neurotoxic microglial activation, particularly in the case of Parkinson's disease. We review the mechanisms of neurotoxicity associated with chronic microglial activation and discuss the role of neuronal death and microglial ROS driving the chronic and toxic microglial phenotype.

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Available from: Melinda E Lull, Apr 28, 2014
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    • "TMT treatments of BV-2 cells because these factors have been reported to participate with NF-í µí¼…B activation in the responses to various stimuli [15] [17]. First, we examined iNOS expression at 12 hr by western blot analysis (Figure 6(a)). "
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    ABSTRACT: Trimethyltin (TMT) is known as a potent neurotoxicant that causes neuronal cell death and neuroinflammation, particularly in the hippocampus. Microglial activation is one of the prominent pathological features of TMT neurotoxicity. Nevertheless, it remains unclear how microglial activation occurs in TMT intoxication. In this study, we aimed to investigate the signaling pathways in TMT-induced microglial activation using BV-2 murine microglial cells. Our results revealed that TMT generates reactive oxygen species (ROS) and increases the expression of CD11b and nuclear factor-κB- (NF-κB-) mediated nitric oxide (NO) and tumor necrosis factor- (TNF-) α in BV-2 cells. We also observed that NF-κB activation was controlled by p38 and JNK phosphorylation. Moreover, TMT-induced ROS generation occurred via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in BV-2 cells. Interestingly, treatment with the NADPH oxidase inhibitor apocynin significantly suppressed p38 and JNK phosphorylation and NF-κB activation and ultimately the production of proinflammatory mediators upon TMT exposure. These findings indicate that NADPH oxidase-dependent ROS generation activated p38 and JNK mitogen-activated protein kinases (MAPKs), which then stimulated NF-κB to release proinflammatory mediators in the TMT-treated BV-2 cells.
    Mediators of Inflammation 07/2015; 2015(2):729509. DOI:10.1155/2015/729509 · 3.24 Impact Factor
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    • "This is also referred to as a primed profile. An inflammatory or primed microglia profile is defined by 1) higher baseline expression of markers of inflammation and inflammatory mediators, 2) a lower threshold to be activated and 'switch' to a pro-inflammatory state (Lull and Block, 2010), and 3) an exaggerated inflammatory response following immune activation. This primed phenotype of microglia is detected in models of aging, neurodegenerative disease and traumatic brain injury. "
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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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    • "The capacity of catecholamine neurons to process and display antigens may thus render them selective targets for T cell mediated cell death. These possibilities are consistent with recent demonstrations that microglia can be activated by substances released from degenerating neurons in PD, such as α-syn (Zhang et al., 2007; Béraud et al., 2013) or NM (Zhang et al., 2011, 2013c), and that activated microglia can elicit neurotoxicity (Block et al., 2007; Lull and Block, 2010; Zhao et al., 2013). Both NM and α-syn are found extracellularly in the postmortem brain of PD patients (Double, 2012), a disorder that features high levels of activated microglia in the SN (Foix and Nicolesco, 1925) and high levels of intracellular oxidative stress (Fahn and Sulzer, 2004). "
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    ABSTRACT: Neuronal expression of major histocompatibility complex I (MHC-I) has been implicated in developmental synaptic plasticity and axonal regeneration in the central nervous system (CNS), but recent findings demonstrate that constitutive neuronal MHC-I can also be involved in neurodegenerative diseases by playing a neuroinflammtory role. Recent reports demonstrate its expression in vitro and in human postmortem samples and support a role in neurodegeneration involving proinflammatory cytokines, activated microglia and increased cytosolic oxidative stress. Major histocompatibility complex I may be important for both normal development and pathogenesis of some CNS diseases including Parkinson's.
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