Astrocytes: Biology and pathology

Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1763, USA.
Acta Neuropathologica (Impact Factor: 10.76). 12/2009; 119(1):7-35. DOI: 10.1007/s00401-009-0619-8
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Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions.

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Available from: Michael V Sofroniew,
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    • "They act as crucial effectors of the neuroinflammatory response (Ransohoff and Brown, 2012). Indeed, astrocytes rapidly act in response to pathology undergoing important changes in their morphology and functioning (Sofroniew and Vinters, 2010; Scuderi et al., 2013; Rossi, 2015). This reactive state starts with the intention to control and remove the brain damage, however it has deleterious consequences. "
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    • "Astrocytes play important roles in development, blood flow, homeostasis, synaptic function, metabolism, and formation of the blood brain barrier (Sofroniew and Vinters, 2010). In ALS, astrocytes become activated in a process called reactive astrogliosis, in which astrocytes become hypertrophic and release increased levels of chemokines and cytokines (Blackburn et al., 2009; Philips and Robberecht, 2011). "
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    ABSTRACT: Astrocytes are key players in the progression of amyotrophic lateral sclerosis (ALS). Previously, gene expression profiling of astrocytes from the pre-symptomatic stage of the SOD1G93A model of ALS has revealed reduced lactate metabolism and altered trophic support. Here, we have performed microarray analysis of symptomatic and late-stage disease astrocytes isolated by laser capture microdissection (LCM) from the lumbar spinal cord of the SOD1G93A mouse to complete the picture of astrocyte behavior throughout the disease course. Astrocytes at symptomatic and late-stage disease show a distinct up-regulation of transcripts defining a reactive phenotype, such as those involved in the lysosome and phagocytic pathways. Functional analysis of hexosaminidase B enzyme activity in the spinal cord and of astrocyte phagocytic ability has demonstrated a significant increase in lysosomal enzyme activity and phagocytic activity in SOD1G93A vs. littermate controls, validating the findings of the microarray study. In addition to the increased reactivity seen at both stages, astrocytes from late-stage disease showed decreased expression of many transcripts involved in cholesterol homeostasis. Staining for the master regulator of cholesterol synthesis, SREBP2, has revealed an increased localization to the cytoplasm of astrocytes and motor neurons in late-stage SOD1G93A spinal cord, indicating that down-regulation of transcripts may be due to an excess of cholesterol in the CNS during late-stage disease possibly due to phagocytosis of neuronal debris. Our data reveal that SOD1G93A astrocytes are characterized more by a loss of supportive function than a toxic phenotype during ALS disease progression and future studies should focus upon restorative therapies. © 2015 Baker, Blackburn, Keatinge, Sokhi, Viskaitis, Heath, Ferraiuolo, Kirby and Shaw.
    Frontiers in Cellular Neuroscience 10/2015; 9(410). DOI:10.3389/fncel.2015.00410 · 4.29 Impact Factor
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    • "Glial pathology occurs in the ageing brain and is a major contributor to age-related neurodegeneration [26] [38]. Astrocytes play a key role maintaining homeostasis in the CNS, including the uptake and recycling of neurotransmitters such as glutamate [20]. "
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    ABSTRACT: The accumulation of reactive oxygen species leading to oxidative damage and cell death plays an important role in a number of neurodegenerative disorders. FOXO3a, the main isoform of FOXO transcription factors, mediates the cellular response to oxidative stress by regulating the expression of genes involved in DNA repair and glutamine metabolism, including glutamine synthetase (GS). Immunohistochemical investigation of the population-based neuropathology cohort of the Medical Research Council's Cognitive Function and Ageing Study (MRC CFAS) demonstrates that nuclear retention of FOXO3a significantly correlates with a DNA damage response and with GS expression by astrocytes. Furthermore, we show that GS expression correlates with increasing Alzheimer-type pathology in this ageing cohort. Our findings suggest that in response to oxidative stress, the nuclear retention of FOXO3a in astrocytes upregulates expression of GS as a neuroprotective mechanism. However, the activity of GS may be compromised by increasing levels of oxidative stress in the ageing brain resulting in dysfunctional enzyme activity, neuronal excitotoxic damage and cognitive impairment.
    Neuroscience Letters 10/2015; 609. DOI:10.1016/j.neulet.2015.10.001 · 2.03 Impact Factor
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