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Astrocytes in Neurodegenerative Disease Nicholas J Maragakis* and Jeffrey D Rothstein

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Astrocytes in Neurodegenerative Disease Nicholas J Maragakis* and Jeffrey D Rothstein REVIEW www.nature.com/clinicalpractice/neuro Mechanisms of Disease: astrocytes in neurodegenerative disease Nicholas J Maragakis* and Jeffrey D Rothstein SUMMARY INTRODUCTION Until relatively recently, astrocytes, along with The term neurodegenerative disease refers to the principal pathology other cells of the glial lineage such as oligodendro- associated with disorders such as amyotrophic lateral sclerosis, Alzheimer’s cytes and microglia, were believed to be structural disease, Huntington’s disease and Parkinson’s disease, and it is presumed cells, the main function of which was to hold that neurodegeneration results in the clinical findings seen in patients neurons together. It is now known, however, that with these diseases. Decades of pathological and physiological studies have focused on neuronal abnormalities in these disorders, but it is becoming astrocytes serve many housekeeping functions, increasingly evident that astrocytes are also important players in these and including maintenance of the extra cellular environ- other neurological disorders. Our understanding of the normative biology ment and stabilization of cell–cell communica- of astrocytes has been aided by the development of animal models in which tions in the CNS. The function of astrocytes in astrocyte-specific proteins and pathways have been manipulated, and regulating cerebral blood flow and maintaining mouse models of neurodegenerative diseases have also revealed astrocyte- synaptic function is becoming increasingly specific pathologies that contribute to neurodegeneration. These models recognized as being of paramount importance in have led to the development of targeted therapies for pathways in which the maintenance of the neuronal environment. astrocytes participate, and this research should ultimately influence the Astrocytes are also central to the maintenance clinical treatment of neurodegenerative disorders. of neuronal metabolism and neurotransmitter synthesis. Understanding these functions has KEYWORDS astrocytes, glia, glial fibrillary acidic protein, glutamate, neurodegenerative disease allowed a refocusing with regard to the role of astrocytes in neurodegenerative diseases, REVIEW CRITERIA which has led to astrocyte-specific analyses with PubMed was searched using Entrez for articles published up to 30 May 2006, potential for drug discovery. including electronic early release publications. Search terms included “astrocyte and neurodegeneration” and “astrocytosis and neurodegeneration”. Phrases combining “astrocytes” with individual neurodegenerative disorders, for CELLULAR FUNCTIONS OF ASTROCYTES example, “astrocyte and Alzheimer’s disease”, were also included in the search. We will begin by highlighting a subset of the The abstracts of retrieved citations were reviewed and prioritized by relevant many cellular functions of astrocytes, focusing content. Full articles were obtained and references were checked for additional specifically on those functions that have the material where appropriate. most relevance to neurodegeneration (Figure 1). Other astrocytic functions, which are beyond the scope of this Review, include the regulation of cell volume, structural support, and the release of neurotransmitters other than glutamate. Amino acid, nutrient and ion metabolism in the brain NJ Maragakis is an assistant professor of neurology, and JD Rothstein is Astrocytes are central to the catabolism of Professor of Neurology and Neuroscience and a member of the Program in selected amino acids in the brain, as well as to Cellular and Molecular Medicine, both at the Johns Hopkins University the synthesis of new amino acids. The produc- School of Medicine, Baltimore, MD, USA. tion of longer carbon backbones in the brain can only occur in astrocytes, owing to the selective Correspondence *Department of Neurology, Johns Hopkins University School of Medicine, 600 N Wolfe Street, localization of pyruvate carboxylase, the only Meyer 6-119, Baltimore, MD 21287, USA brain enzyme capable of replenishing molecular [email protected] intermediates for other metabolic reactions. Astrocytes transport various nutrient and Received 19 July 2006 Accepted 21 September 2006 www.nature.com/clinicalpractice meta bolic precursors to neurons via the malate– doi:10.1038/ncpneuro0355 aspartate shuttle. One of the most important DECEMBER 2006 VOL 2 NO 12 NATURE CLINICAL PRACTICE NEUROLOGY 679 © 2006 Nature Publishing Group nncpneuro_2006_144.inddcpneuro_2006_144.indd 667979 331/10/061/10/06 111:15:301:15:30 aamm REVIEW www.nature.com/clinicalpractice/neuro Neuron Gln Normal astrocyte Glu Glu 9 1 4 Gap junction Intermediate filaments Glu Gln 8 Glutamate transporter IP3 2 PLC ? Glucose transporter 2+ 7 IP3/Ca mGlu receptor 2+ IP3/Ca Purine receptor Ca2+ 3 Hemichannels Ca2+ ATP Glucose Gap junctions 6 Glutamate Vasoactive substances (prostaglandin E2 epoxyeicosatrienoic acids, 5 nitric oxide or adenosine) Figure 1 Normal functions of astrocytes. (1) Astrocyte functions include modulation of synaptic function via glutamate transporters, which convey glutamate from the synaptic cleft into the cell.1 (2) Communication between astrocytes occurs via ATP release and binding to purine receptors on adjacent astrocytes.14 ATP binding results in phospholipase C activation, with subsequent downstream activation of inositol trisphosphate, resulting in calcium mobilization. (3) Gap junctions contribute to an astrocyte syncytium for the exchange of small molecules and cell–cell communication.14 Metabolic functions include (4) the replenishment of neuronal glutamate via the glutamate– glutamine cycle, and (5) the transport of glucose from the vasculature.1 (6) The regulation of blood flow is modulated by astrocyte end-feet apposing blood vessels, with vasodilation being mediated through release of vasoactive substances.3,4 (7) Glutamate release might occur following elevations in intracellular calcium and the activation of other factors related to prostaglandins.12 (8) Glutamate release through hemichannels can be induced in vitro through lowering of extracellular calcium.13 (9) Glutamate binding to metabotropic glutamate receptors activates intracellular calcium, leading to the release of vasodilatory substances.4 Abbreviations: Gln, glutamine; Glu, glutamate; IP3, inositol trisphosphate; PLC, phospholipase C. metabolic links between neurons and astro- occurs through potassium channels expressed cytes, however, is the glutamate–glutamine by astrocytes at synapses and at end-foot shuttle. Astrocytes transport the vast majority pro cesses around capillaries. of extracellular glutamate (especially neuro- transmitter pools) and convert it to glutamine. Coupling of neuronal activity and cerebral This glutamine is shuttled back to presynaptic blood flow terminals, and is critical for the synthesis of the Evidence is accumulating that astrocytes have neurotransmitter glutamate. Astrocytes also an important function in cerebrovascular regu- convert glucose to lactic acid, which is subse- lation. Astrocytic processes have end-feet with quently taken up into neurons and converted contact to the brain vasculature, and they envelop to pyruvate for energy metabolism.1 neuronal synapses. The relationship between Astrocytes have an important role in the regu- neurons, astrocytes and blood vessels makes lation of ion concentrations in the intracellular astrocytes a central element that can modulate and extracellular spaces in the brain. Carbon neuronal activity and cerebral blood flow. In dioxide is produced by neurons following the vitro and in vivo studies of cortical tissue indi- oxidative metabolism of pyruvate. Astrocytes cate that synaptic release of glutamate activates regulate acid–base balance via carbonic metabotropic glutamate receptors on astrocytes. an hydrase, which converts carbon dioxide and These receptors trigger the release of arachidonic water to hydrogen ions and bi carbonate ions. acid metabolites,3 leading to a localized increase Extracellular potassium also accumulates from in calcium at astrocyte end-feet, which results in neural activity,2 and buffering of potassium dilation of nearby arterioles.4 680 NATURE CLINICAL PRACTICE NEUROLOGY MARAGAKIS AND ROTHSTEIN DECEMBER 2006 VOL 2 NO 12 © 2006 Nature Publishing Group nncpneuro_2006_144.inddcpneuro_2006_144.indd 668080 331/10/061/10/06 111:15:331:15:33 aamm REVIEW www.nature.com/clinicalpractice/neuro Modulation of excitatory synaptic adjacent astrocyte through connexin 43 (Cx43) transmission gap junctions, thereby producing a calcium wave Glutamate is the primary excitatory neuro- through an astrocyte syncytium. IP3 also activates transmitter in the CNS, and its activity is carefully ATP release through Cx43 hemichannels. This regulated by both neuronal and glial influences. ATP release acts in a paracrine fashion, activating The majority of synaptic and perisynaptic gluta- purine receptors on adjacent astrocytes. This acti- mate regulation occurs through glutamate trans- vation results in IP3 production, more ATP release porters. In addition to the tightly coupled synaptic and intracellular calcium mobilization through a relationship between neuronal synapses and feed-forward mechanism.14 astrocytes, astrocyte-to-astrocyte transmission through gap junctions, as well as paracrine release ASTROCYTE-SPECIFIC PATHOLOGY: of ATP, might modulate synaptic biology. LESSONS FROM MOUSE MODELS Transgenic and knockout mice have been valuable Regulation of glutamate transport in helping us to understand the patho physiology Glutamate transport
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