Neuroglia in neurodegeneration

Neuroglial cells are fundamental for control of brain homeostasis and they represent the intrinsic brain defence system. All forms in neuropathology therefore inevitably involve glia. The neurodegenerative diseases disrupt connectivity within brain circuits affecting neuronal-neuronal, neuronal-glial and glial-glial contacts. In addition neurodegenerative processes trigger universal and conserved glial reactions represented by astrogliosis and microglial activation. The complex of recently acquired knowledge allows us to regard the neurodegenerative diseases as primarily gliodegenerative processes, in which glial cells determine the progression and outcome of neuropathological process.

[1]  M. Mena,et al.  Glial Cells as Players in Parkinsonism: The “Good,” the “Bad,” and the “Mysterious” Glia , 2008, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[2]  S. Oliet,et al.  Regulation of N-methyl-d-aspartate receptors by astrocytic d-serine , 2009, Neuroscience.

[3]  J. Hell,et al.  Thrombospondins Are Astrocyte-Secreted Proteins that Promote CNS Synaptogenesis , 2005, Cell.

[4]  Mark Ellisman,et al.  Protoplasmic Astrocytes in CA1 Stratum Radiatum Occupy Separate Anatomical Domains , 2002, The Journal of Neuroscience.

[5]  A. Verkhratsky,et al.  Neuronal-glial networks as substrate for CNS integration , 2006, Journal of cellular and molecular medicine.

[6]  G. Levi,et al.  Up‐regulation of Cyclooxygenase‐2 Expression in Cultured Microglia by Prostaglandin E2, Cyclic AMP and Non‐steroidal Anti‐inflammatory Drugs , 1997, The European journal of neuroscience.

[7]  B. MacVicar,et al.  Calcium transients in astrocyte endfeet cause cerebrovascular constrictions , 2004, Nature.

[8]  T. Klockgether,et al.  Neuronal and Glial Coexpression of Argininosuccinate Synthetase and Inducible Nitric Oxide Synthase in Alzheimer Disease , 2001, Journal of neuropathology and experimental neurology.

[9]  Serge Charpak,et al.  GABA, a forgotten gliotransmitter , 2008, Progress in Neurobiology.

[10]  J. Coyle,et al.  Glutamatergic mechanisms in schizophrenia. , 2003, Annual review of pharmacology and toxicology.

[11]  T. Takano,et al.  Astrocyte-mediated control of cerebral blood flow , 2006, Nature Neuroscience.

[12]  G. Rosoklija,et al.  Increased expression of the pro‐inflammatory enzyme cyclooxygenase‐2 in amyotrophic lateral sclerosis , 2001, Annals of neurology.

[13]  P. Mcgeer,et al.  The possible role of complement activation in Alzheimer disease. , 2002, Trends in molecular medicine.

[14]  M. Sawada,et al.  Inflammatory process in Parkinson's disease: role for cytokines. , 2005, Current pharmaceutical design.

[15]  M. Simard,et al.  The neurobiology of glia in the context of water and ion homeostasis , 2004, Neuroscience.

[16]  S. Amor,et al.  Preactive lesions in multiple sclerosis , 2009, Current opinion in neurology.

[17]  Masahiko Watanabe,et al.  Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. , 1997, Science.

[18]  A. Floden,et al.  β-Amyloid Stimulates Murine Postnatal and Adult Microglia Cultures in a Unique Manner , 2006, The Journal of Neuroscience.

[19]  E. Newman,et al.  Potassium buffering in the central nervous system , 2004, Neuroscience.

[20]  G. Struhl,et al.  Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb , 1998, Nature.

[21]  G. Cole,et al.  The microglial phagocytic role with specific plaque types in the Alzheimer disease brain , 2004, Neurobiology of Aging.

[22]  A. Cornell-Bell,et al.  Human epileptic astrocytes exhibit increased gap junction coupling , 1995, Glia.

[23]  Eric A Newman,et al.  Glial Cells Dilate and Constrict Blood Vessels: A Mechanism of Neurovascular Coupling , 2006, The Journal of Neuroscience.

[24]  M. Berry,et al.  Cytology and lineage of NG2-positive glia , 2002, Journal of neurocytology.

[25]  V. Gallo,et al.  NG2‐positive cells in the mouse white and grey matter display distinct physiological properties , 2004, The Journal of physiology.

[26]  J. Ojemann,et al.  Uniquely Hominid Features of Adult Human Astrocytes , 2009, The Journal of Neuroscience.

[27]  D. Bergles,et al.  Physiological characteristics of NG2-expressing glial cells , 2002, Journal of neurocytology.

[28]  Christian Steinhäuser,et al.  Astrocytic function and its alteration in the epileptic brain , 2008, Epilepsia.

[29]  Tony Wyss-Coray,et al.  Inflammation in Neurodegenerative Disease—A Double-Edged Sword , 2002, Neuron.

[30]  Kenneth J. Smith,et al.  Factors directly affecting impulse transmission in inflammatory demyelinating disease: recent advances in our understanding , 2001, Current opinion in neurology.

[31]  D. Gutmann,et al.  Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis , 2008, Nature Neuroscience.

[32]  Jm Charcot,et al.  Deux cas d’atrophie musculaire progressive avec lesions de la substance grise et des faisceaux antero-lateraux de la moelle epiniere , 1869 .

[33]  I. Blumenthal,et al.  Periventricular leucomalacia: a review , 2004, European Journal of Pediatrics.

[34]  Ted M. Dawson,et al.  Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease , 1999, Nature Medicine.

[35]  C. Schleich Schmerzlose Operationen: Örtliche Betäubung mit indifferenten Flüssigkeiten. Psychophysik des natürlichen und künstlichen Schlafes , 1906 .

[36]  James Parkinson,et al.  An essay on the shaking palsy. 1817. , 2002, The Journal of neuropsychiatry and clinical neurosciences.

[37]  D. Spencer,et al.  Loss of perivascular aquaporin 4 may underlie deficient water and K+ homeostasis in the human epileptogenic hippocampus. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[38]  M. Mattson,et al.  Triple-Transgenic Model of Alzheimer's Disease with Plaques and Tangles Intracellular Aβ and Synaptic Dysfunction , 2003, Neuron.

[39]  Michael T. Heneka,et al.  Inflammatory processes in Alzheimer's disease , 2007, Journal of Neuroimmunology.

[40]  Stephen J. Smith,et al.  Neuronal activity triggers calcium waves in hippocampal astrocyte networks , 1992, Neuron.

[41]  C. Ferrari,et al.  Central and systemic IL-1 exacerbates neurodegeneration and motor symptoms in a model of Parkinson's disease , 2008, Brain : a journal of neurology.

[42]  Alexei Verkhratsky,et al.  Neuroglia: the 150 years after , 2008, Trends in Neurosciences.

[43]  C. Heyser,et al.  Progressive decline in avoidance learning paralleled by inflammatory neurodegeneration in transgenic mice expressing interleukin 6 in the brain. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[44]  A. Pramatarova,et al.  Neuron-Specific Expression of Mutant Superoxide Dismutase 1 in Transgenic Mice Does Not Lead to Motor Impairment , 2001, The Journal of Neuroscience.

[45]  P. Haydon,et al.  Physiological astrocytic calcium levels stimulate glutamate release to modulate adjacent neurons. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[46]  G. Kollias,et al.  CXCR4-activated astrocyte glutamate release via TNFα: amplification by microglia triggers neurotoxicity , 2001, Nature Neuroscience.

[47]  D. Spray,et al.  Connexin43 null mice reveal that astrocytes express multiple connexins , 2000, Brain Research Reviews.

[48]  R. Leech,et al.  Thalamic dementia: an example of primary astroglial dystrophy of Seitelberger. , 2005, Clinical neuropathology.

[49]  B. Roth,et al.  Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression∗ ∗ See accompanying Editorial, in this issue. , 1999, Biological Psychiatry.

[50]  Q. Wang,et al.  PGE2 receptors rescue motor neurons in a model of amyotrophic lateral sclerosis , 2004, Annals of neurology.

[51]  D. Middleton,et al.  Association between polymorphism in regulatory region of gene encoding tumour necrosis factor α and risk of Alzheimer's disease and vascular dementia: a case-control study , 2001, The Lancet.

[52]  Santiago Canals,et al.  The role of astroglia on the survival of dopamine neurons , 2002, Molecular Neurobiology.

[53]  M. Norenberg,et al.  Glutamine synthetase: glial localization in brain , 1977, Science.

[54]  M. Ato,et al.  Amelioration of experimental autoimmune encephalomyelitis in C57BL/6 mice by an agonist of peroxisome proliferator-activated receptor-γ , 2001, Journal of Neuroimmunology.

[55]  D. Dickson,et al.  Microglia and cytokines in neurological disease, with special reference to AIDS and Alzheimer's disease , 1993, Glia.

[56]  J. Kershman GENESIS OF MICROGLIA IN THE HUMAN BRAIN , 1939 .

[57]  Jose Julio Rodriguez,et al.  Astroglia in dementia and Alzheimer's disease , 2009, Cell Death and Differentiation.

[58]  Michael M. Halassa,et al.  The tripartite synapse: roles for gliotransmission in health and disease. , 2007, Trends in molecular medicine.

[59]  S. Barger,et al.  Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E , 1997, Nature.

[60]  M. D. de Bellard,et al.  Glial cells: old cells with new twists. , 2008, Acta histochemica.

[61]  S. Roßner,et al.  Alzheimer's disease β‐secretase BACE1 is not a neuron‐specific enzyme , 2005 .

[62]  K. Nave,et al.  NG2‐expressing cells in the nervous system revealed by the NG2‐EYFP‐knockin mouse , 2008, Genesis.

[63]  M. Mena,et al.  The effect of glia-conditioned medium on dopamine neurons in culture. Modulation of apoptosis, tyrosine hydroxylase expression and 1-methyl-4-phenylpyridinium toxicity , 1999, Journal of Neural Transmission.

[64]  M. Gurney,et al.  Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. , 1994, Science.

[65]  Jialin C. Zheng,et al.  Role of activated astrocytes in neuronal damage: Potential links to HIV-1-associated dementia , 2009, Neurotoxicity Research.

[66]  C. Matute P2X7 Receptors in Oligodendrocytes: A Novel Target for Neuroprotection , 2008, Molecular Neurobiology.

[67]  C. B. Kunst,et al.  Complex genetics of amyotrophic lateral sclerosis. , 2004, American journal of human genetics.

[68]  R. Jabs,et al.  Lack of P2X receptor mediated currents in astrocytes and GluR type glial cells of the hippocampal CA1 region , 2007, Glia.

[69]  S. Przedborski,et al.  Inducible Nitric Oxide Synthase Up‐Regulation in a Transgenic Mouse Model of Familial Amyotrophic Lateral Sclerosis , 1999, Journal of neurochemistry.

[70]  B. Seed,et al.  PPAR-γ agonists inhibit production of monocyte inflammatory cytokines , 1998, Nature.

[71]  T. Montine,et al.  Deletion of the Prostaglandin E2 EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease , 2005, The Journal of Neuroscience.

[72]  A. Araque,et al.  Tripartite synapses: glia, the unacknowledged partner , 1999, Trends in Neurosciences.

[73]  S. Gobbo,et al.  Astrocytic Glutamate Is Not Necessary for the Generation of Epileptiform Neuronal Activity in Hippocampal Slices , 2006, The Journal of Neuroscience.

[74]  G. Landreth,et al.  β-Amyloid Stimulation of Microglia and Monocytes Results in TNFα-Dependent Expression of Inducible Nitric Oxide Synthase and Neuronal Apoptosis , 2001, The Journal of Neuroscience.

[75]  H. Kettenmann,et al.  Membrane currents and cytoplasmic sodium transients generated by glutamate transport in Bergmann glial cells , 2007, Pflügers Archiv - European Journal of Physiology.

[76]  M. Schwartz,et al.  Activation of microglia by aggregated β-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-γ and IL-4 render them protective , 2005, Molecular and Cellular Neuroscience.

[77]  J. Langeveld,et al.  Activation of human microglia by fibrillar prion protein-related peptides is enhanced by amyloid-associated factors SAP and C1q , 2005, Neurobiology of Disease.

[78]  C. Plata-salamán,et al.  Inflammation and Alzheimer’s disease , 2000, Neurobiology of Aging.

[79]  L. Schweitzer,et al.  Expression of chemokine receptors by subsets of neurons in the central nervous system. , 1997, Journal of immunology.

[80]  Pierre J Magistretti,et al.  Role of glutamate in neuron-glia metabolic coupling. , 2009, The American journal of clinical nutrition.

[81]  B. Hyman,et al.  Immunohistochemical Study of the β-Chemokine Receptors CCR3 and CCR5 and Their Ligands in Normal and Alzheimer's Disease Brains , 1998 .

[82]  M. D'Andrea,et al.  Astrocytes accumulate Aβ42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains , 2003, Brain Research.

[83]  P. Mcgeer,et al.  Inflammatory processes in amyotrophic lateral sclerosis , 2002, Muscle & nerve.

[84]  V. Bigl,et al.  Astrocytic expression of the Alzheimer's disease β‐secretase (BACE1) is stimulus‐dependent , 2003, Glia.

[85]  A. Kölliker Handbuch der Gewebelehre des Menschen : für Aerzte und Studirende , 1863 .

[86]  C. Sherrington,et al.  On the Regulation of the Blood‐supply of the Brain , 1890, The Journal of physiology.

[87]  M. Kavanaugh,et al.  Flux coupling in a neuronal glutamate transporter , 1996, Nature.

[88]  A. Nishiyama,et al.  Polydendrocytes (NG2 cells): multifunctional cells with lineage plasticity , 2009, Nature Reviews Neuroscience.

[89]  Pierre J Magistretti,et al.  Neuron-glia metabolic coupling and plasticity. , 2006, The Journal of experimental biology.

[90]  M. Duchen,et al.  Changes in Intracellular Calcium and Glutathione in Astrocytes as the Primary Mechanism of Amyloid Neurotoxicity , 2003, The Journal of Neuroscience.

[91]  U. Hanisch,et al.  Microglia as a source and target of cytokines , 2002, Glia.

[92]  S. Finkbeiner,et al.  Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. , 1990, Science.

[93]  S. Kirischuk,et al.  Na+/Ca2+ exchanger modulates kainate‐triggered Ca2+ signaling in Bergmann glial cells in situ , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[94]  C. Weigert Beiträge zur Kenntnis der normalen menschlichen Neuroglia : Festschrift zum fünfzigjährigen Jubiläum des ärztlichen Vereins zu Frankfurt a. M., 3. November 1895 , 1895 .

[95]  P. Heinrich,et al.  Interleukin‐6 is the major regulator of acute phase protein synthesis in adult human hepatocytes , 1989, FEBS letters.

[96]  M. Lenhossék Der feinere Bau des Nervensystems im Lichte neuester Forschungen , 1893 .

[97]  M. Hüll,et al.  Microglial expression of prostaglandin EP3 receptor in excitotoxic lesions in the rat striatum , 2004, Neurochemistry International.

[98]  Holger Heine,et al.  Role of the Toll-Like Receptor 4 in Neuroinflammation in Alzheimer’s Disease , 2007, Cellular Physiology and Biochemistry.

[99]  F. Turkheimer,et al.  Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study , 2004, Neurobiology of Disease.

[100]  V. Gundersen,et al.  Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate , 2004, Nature Neuroscience.

[101]  P. Carmeliet,et al.  Protective Role of Reactive Astrocytes in Brain Ischemia , 2008, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[102]  R. North,et al.  NMDA Receptors Mediate Neuron-to-Glia Signaling in Mouse Cortical Astrocytes , 2006, The Journal of Neuroscience.

[103]  J. Levine,et al.  Localization of a neurectoderm-associated cell surface antigen in the developing and adult rat. , 1986, Brain research.

[104]  Ling Li,et al.  Role of toll-like receptor signalling in Abeta uptake and clearance. , 2006, Brain : a journal of neurology.

[105]  C. Iadecola,et al.  Glial regulation of the cerebral microvasculature , 2007, Nature Neuroscience.

[106]  J. Meldolesi,et al.  Astrocytes, from brain glue to communication elements: the revolution continues , 2005, Nature Reviews Neuroscience.

[107]  Nicholas Lange,et al.  D-serine added to antipsychotics for the treatment of schizophrenia , 1998, Biological Psychiatry.

[108]  J. Wegiel,et al.  Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease , 2004, Neurobiology of Aging.

[109]  Y. Chong,et al.  Mechanisms involved in prostaglandin E2-mediated neuroprotection against TNF-α: possible involvement of multiple signal transduction and β-catenin/T-cell factor , 2004, Journal of Neuroimmunology.

[110]  Jullie W Pan,et al.  Mesial temporal lobe epilepsy: a proton magnetic resonance spectroscopy study and a histopathological analysis. , 2004, Journal of neurosurgery.

[111]  P. Agostinho,et al.  Amyloid-beta peptide decreases glutamate uptake in cultured astrocytes: Involvement of oxidative stress and mitogen-activated protein kinase cascades , 2008, Neuroscience.

[112]  H. Neumann,et al.  Neuronal ‘On’ and ‘Off’ signals control microglia , 2007, Trends in Neurosciences.

[113]  P. Eikelenboom,et al.  Inflammatory mechanisms in Alzheimer's disease. , 1994, Trends in pharmacological sciences.

[114]  J. Kril,et al.  Astrocytic degeneration relates to the severity of disease in frontotemporal dementia. , 2004, Brain : a journal of neurology.

[115]  K. Nave,et al.  Mechanisms of Disease: inherited demyelinating neuropathies—from basic to clinical research , 2007, Nature Clinical Practice Neurology.

[116]  E. Newman,et al.  Control of extracellular potassium levels by retinal glial cell K+ siphoning. , 1984, Science.

[117]  Joachim W. Deitmer,et al.  Calcium signalling in glial cells , 1998 .

[118]  G. Kreutzberg Microglia: a sensor for pathological events in the CNS , 1996, Trends in Neurosciences.

[119]  S. Oliet,et al.  Glia-Derived d-Serine Controls NMDA Receptor Activity and Synaptic Memory , 2006, Cell.

[120]  P. Grammas,et al.  Inflammatory factors are elevated in brain microvessels in Alzheimer’s disease , 2001, Neurobiology of Aging.

[121]  P. Mcgeer,et al.  The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases , 1995, Brain Research Reviews.

[122]  W. Snider,et al.  Restricted Expression of G86R Cu/Zn Superoxide Dismutase in Astrocytes Results in Astrocytosis But Does Not Cause Motoneuron Degeneration , 2000, The Journal of Neuroscience.

[123]  F. Rossi,et al.  Synergistic Induction of Nitric Oxide by β-Amyloid and Cytokines in Astrocytes , 1996 .

[124]  B. Bergamasco,et al.  Increased intrathecal TGF-β1, but not IL-12, IFN-γ and IL-10 levels in Alzheimer’s disease patients , 2006, Neurological Sciences.

[125]  M. Schultzberg,et al.  β-amyloid protein structure determines the nature of cytokine release from rat microglia , 2007, Journal of Molecular Neuroscience.

[126]  Thomas Klockgether,et al.  Acute treatment with the PPARγ agonist pioglitazone and ibuprofen reduces glial inflammation and Aβ1–42 levels in APPV717I transgenic mice , 2005 .

[127]  S. Ferroni,et al.  Cascading Glia Reactions: a Common Pathomechanism and Its Differentiated Control by Cyclic Nucleotide Signaling , 2000, Annals of the New York Academy of Sciences.

[128]  A. Verkhratsky Patching the glia reveals the functional organisation of the brain , 2006, Pflügers Archiv.

[129]  U. Dirnagl,et al.  Role of glial cells in cerebral ischemia , 2005, Glia.

[130]  Association of interleukin‐1 gene polymorphisms with Alzheimer's disease , 2000, Annals of neurology.

[131]  P. Somogyi,et al.  Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus , 2000, Nature.

[132]  F. Pfrieger,et al.  Marked differences in cholesterol synthesis between neurons and glial cells from postnatal rats , 2009, Journal of neurochemistry.

[133]  L. Mucke,et al.  Chronic overproduction of transforming growth factor-beta1 by astrocytes promotes Alzheimer's disease-like microvascular degeneration in transgenic mice. , 2000, The American journal of pathology.

[134]  C. Brosnan,et al.  Proliferation of astrocytes in vitro in response to cytokines. A primary role for tumor necrosis factor. , 1990, Journal of immunology.

[135]  T. Takano,et al.  An astrocytic basis of epilepsy , 2005, Nature Medicine.

[136]  D. McTigue,et al.  The life, death, and replacement of oligodendrocytes in the adult CNS , 2008, Journal of neurochemistry.

[137]  M. Ilyas Kamboh,et al.  A4POE*4-associated Alzheimer's disease risk is modified by α1–antichymotrypsin polymorphism , 1995, Nature Genetics.

[138]  A. Volterra,et al.  Focal degeneration of astrocytes in amyotrophic lateral sclerosis , 2008, Cell Death and Differentiation.

[139]  A. Volterra,et al.  Astrocytic dysfunction: Insights on the role in neurodegeneration , 2009, Brain Research Bulletin.

[140]  B. Schürmann,et al.  The Oral Antidiabetic Pioglitazone Protects from Neurodegeneration and Amyotrophic Lateral Sclerosis-Like Symptoms in Superoxide Dismutase-G93A Transgenic Mice , 2005, The Journal of Neuroscience.

[141]  P. Gebicke-haerter,et al.  Expression and regulation of cyclooxygenase-2 in rat microglia. , 1997, European journal of biochemistry.

[142]  Michael M. Halassa,et al.  Synaptic Islands Defined by the Territory of a Single Astrocyte , 2007, The Journal of Neuroscience.

[143]  Nathalie Rouach,et al.  Astroglial Metabolic Networks Sustain Hippocampal Synaptic Transmission , 2008, Science.

[144]  Stuart A. Lipton,et al.  Pathways to neuronal injury and apoptosis in HIV-associated dementia , 2001, Nature.

[145]  A. Butt Structure and function of oligodendrocytes , 2004 .

[146]  F. Kirchhoff,et al.  Glia: the fulcrum of brain diseases , 2007, Cell Death and Differentiation.

[147]  A. Aloisi,et al.  Cognitive function in young and adult IL (interleukin)-6 deficient mice , 2004, Behavioural Brain Research.

[148]  Andriezen Wl,et al.  The Neuroglia Elements in the Human Brain , 1893 .

[149]  A. Hazell Astrocytes are a major target in thiamine deficiency and Wernicke's encephalopathy , 2009, Neurochemistry International.

[150]  L. Barbeito,et al.  A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis , 2004, Brain Research Reviews.

[151]  P. Ince,et al.  Expression of nitric oxide synthase isoforms in spinal cord in amyotrophic lateral sclerosis , 2000 .

[152]  J. Trojanowski,et al.  Transgenic Mouse Model of Tau Pathology in Astrocytes Leading to Nervous System Degeneration , 2005, The Journal of Neuroscience.

[153]  T Suenaga,et al.  Alterations in glia and axons in the brains of Binswanger's disease patients. , 1997, Stroke.

[154]  M. C. Angulo,et al.  Target cell-specific modulation of neuronal activity by astrocytes. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[155]  M. Botto C1q Knock-Out Mice for the Study of Complement Deficiency in Autoimmune Disease , 1999, Experimental and Clinical Immunogenetics.

[156]  C. Théry,et al.  Interleukin 1 and tumor necrosis factor-alpha stimulate the production of colony-stimulating factor 1 by murine astrocytes. , 1992, Journal of neurochemistry.

[157]  P. Eikelenboom,et al.  Neuroinflammatory perspectives on the two faces of Alzheimer’s disease , 2004, Journal of Neural Transmission.

[158]  David Boltz,et al.  Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration , 2009, Proceedings of the National Academy of Sciences.

[159]  A. Troncoso,et al.  Regional differences in astrocyte activation in HIV-associated dementia. , 2006, Medicina.

[160]  Sung-Chun Tang,et al.  Toll-like receptors in neurodegeneration , 2009, Brain Research Reviews.

[161]  Thomas Klockgether,et al.  Nonsteroidal Anti-Inflammatory Drugs and Peroxisome Proliferator-Activated Receptor-γ Agonists Modulate Immunostimulated Processing of Amyloid Precursor Protein through Regulation of β-Secretase , 2003, The Journal of Neuroscience.

[162]  H. Hampel,et al.  Inflammatory repertoire of Alzheimer's disease and nondemented elderly microglia in vitro , 2001, Glia.

[163]  G. Landreth,et al.  Regulation of β-amyloid stimulated proinflammatory responses by peroxisome proliferator-activated receptor α , 2001, Neurochemistry International.

[164]  W. Gan,et al.  ATP mediates rapid microglial response to local brain injury in vivo , 2005, Nature Neuroscience.

[165]  M. Rattray,et al.  NG2 cells differentiate into astrocytes in cerebellar slices , 2009, Molecular and Cellular Neuroscience.

[166]  Michal Schwartz,et al.  The bright side of the glial scar in CNS repair , 2009, Nature Reviews Neuroscience.

[167]  H. Kettenmann,et al.  Microglia: active sensor and versatile effector cells in the normal and pathologic brain , 2007, Nature Neuroscience.

[168]  M. Landt,et al.  Analysis of Cerebrospinal Fluid Glial Fibrillary Acidic Protein after Seizures in Children , 2003, Epilepsia.

[169]  W. Stallcup The NG2 proteoglycan: Past insights and future prospects , 2002, Journal of neurocytology.

[170]  Ana Gadea,et al.  Glial transporters for glutamate, glycine and GABA I. Glutamate transporters , 2001, Journal of neuroscience research.

[171]  D. Feinstein,et al.  Expression and function of inducible nitric oxide synthase in neurons , 2001, Journal of Neuroimmunology.

[172]  Khaleel Bhaukaurally,et al.  Glutamate exocytosis from astrocytes controls synaptic strength , 2007, Nature Neuroscience.

[173]  Frank W Pfrieger,et al.  New views on synapse—glia interactions , 1996, Current Opinion in Neurobiology.

[174]  L. Fetler,et al.  Brain Under Surveillance: The Microglia Patrol , 2005, Science.

[175]  A. Alzheimer,et al.  Histologische und histopathologische Arbeiten über die Grosshirnrinde : mit besonderer Berücksichtigung der pathologischen Anatomie der Geisteskrankheiten , 1904 .

[176]  Bin Liu,et al.  Role of Microglia in Inflammation-Mediated Neurodegenerative Diseases: Mechanisms and Strategies for Therapeutic Intervention , 2003, Journal of Pharmacology and Experimental Therapeutics.

[177]  Geoffrey Burnstock,et al.  Purinergic signalling in the nervous system: an overview , 2009, Trends in Neurosciences.

[178]  M. Mena,et al.  Glia conditioned medium protects fetal rat midbrain neurones in culture from L‐DOPA toxicity , 1996, Neuroreport.

[179]  G. Burnstock,et al.  Purinoceptors on Neuroglia , 2009, Molecular Neurobiology.

[180]  M. Nilsson,et al.  Astrocyte activation and reactive gliosis , 2005, Glia.

[181]  B. Barres,et al.  Thrombospondins 1 and 2 are Necessary for Synaptic Plasticity and Functional Recovery after Stroke , 2008, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[182]  Cathryn L. Kubera,et al.  Astrocytic Purinergic Signaling Coordinates Synaptic Networks , 2005, Science.

[183]  J. Wiltfang,et al.  Amyloid beta peptide 1–40 enhances the action of Toll‐like receptor‐2 and ‐4 agonists but antagonizes Toll‐like receptor‐9‐induced inflammation in primary mouse microglial cell cultures , 2005, Journal of neurochemistry.

[184]  G. Pasinetti,et al.  A therapeutic role for cyclooxygenase‐2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[185]  E. Hirsch,et al.  Protective action of the peroxisome proliferator‐activated receptor‐γ agonist pioglitazone in a mouse model of Parkinson's disease , 2002, Journal of neurochemistry.

[186]  D. Attwell,et al.  The ionic stoichiometry of the GLAST glutamate transporter in salamander retinal glia , 2006, The Journal of physiology.

[187]  D. Attwell,et al.  Glutamate release in severe brain ischaemia is mainly by reversed uptake , 2000, Nature.

[188]  A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. , 2000 .

[189]  T. Wyss-Coray,et al.  Adult mouse astrocytes degrade amyloid-β in vitro and in situ , 2003, Nature Medicine.

[190]  P. Caroni,et al.  Accumulation of SOD1 Mutants in Postnatal Motoneurons Does Not Cause Motoneuron Pathology or Motoneuron Disease , 2002, The Journal of Neuroscience.

[191]  G. Kroemer,et al.  Cell death mechanisms in HIV-associated dementia: the involvement of syncytia , 2005, Cell Death and Differentiation.

[192]  A. Verkhratsky Calcium ions and integration in neural circuits , 2006, Acta physiologica.

[193]  A. Hazell,et al.  Loss of astrocytic glutamate transporters in Wernicke encephalopathy , 2010, Glia.

[194]  Rhona Mirsky,et al.  Negative regulation of myelination: Relevance for development, injury, and demyelinating disease , 2008, Glia.

[195]  F. Kirchhoff,et al.  Glutamate‐mediated neuronal–glial transmission , 2007, Journal of anatomy.

[196]  J. Kril,et al.  Regional and cellular pathology in frontotemporal dementia: relationship to stage of disease in cases with and without Pick bodies , 2004, Acta Neuropathologica.

[197]  S. Goldman,et al.  Astrocytic complexity distinguishes the human brain , 2006, Trends in Neurosciences.

[198]  S. Lockett,et al.  Activation of Toll-like Receptor 2 on Microglia Promotes Cell Uptake of Alzheimer Disease-associated Amyloid β Peptide* , 2006, Journal of Biological Chemistry.

[199]  M. Beal,et al.  Peroxisome proliferator-activated receptor-gamma agonist extends survival in transgenic mouse model of amyotrophic lateral sclerosis , 2005, Experimental Neurology.

[200]  R. Bruzzone,et al.  Connexins and information transfer through glia. , 1999, Advances in experimental medicine and biology.

[201]  R. Swanson Astrocyte Neurotransmitter Uptake , 2004 .

[202]  P. Gasque,et al.  Activation of Complement in the Central Nervous System , 2003, Annals of the New York Academy of Sciences.

[203]  N. Hamilton,et al.  Synantocytes: the fifth element , 2005, Journal of anatomy.

[204]  Mark Ellisman,et al.  Maturation of astrocyte morphology and the establishment of astrocyte domains during postnatal hippocampal development , 2004, International Journal of Developmental Neuroscience.

[205]  F. Helmchen,et al.  Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma in Vivo , 2005, Science.

[206]  S. Duan,et al.  P2X7 Receptor-Mediated Release of Excitatory Amino Acids from Astrocytes , 2003, The Journal of Neuroscience.

[207]  D. Attwell,et al.  Modulation of extracellular glutamate concentration in rat brain slices by cystine‐glutamate exchange , 1999, The Journal of physiology.

[208]  M. Nedergaard,et al.  Connexin 43 Hemichannels Are Permeable to ATP , 2008, The Journal of Neuroscience.

[209]  T. Klockgether,et al.  Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[210]  Tullio Pozzan,et al.  Prostaglandins stimulate calcium-dependent glutamate release in astrocytes , 1998, Nature.

[211]  K. Moore,et al.  Journal of Neuroinflammation BioMed Central , 2004 .

[212]  T. Hartmann,et al.  TNFα plus IFNγ induce the production of Alzheimer β‐amyloid peptides and decrease the secretion of APPs , 1999 .

[213]  A. Carè,et al.  Production of hemolymphopoietic cytokines (IL-6, IL-8, colony-stimulating factors) by normal human astrocytes in response to IL-1 beta and tumor necrosis factor-alpha. , 1992, Journal of immunology.

[214]  R. North,et al.  P2X1 and P2X5 Subunits Form the Functional P2X Receptor in Mouse Cortical Astrocytes , 2008, The Journal of Neuroscience.

[215]  L R Caplan,et al.  Binswanger's disease. , 1993, Advances in neurology.

[216]  A. Contestabile,et al.  Neuroprotection of microglial conditioned medium on 6‐hydroxydopamine‐induced neuronal death: role of transforming growth factor beta‐2 , 2009, Journal of neurochemistry.

[217]  J. Dichgans,et al.  Deficiency of Inducible Nitric Oxide Synthase Protects Against MPTP Toxicity In Vivo , 2000, Journal of neurochemistry.

[218]  J. Haines,et al.  Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis , 1993, Nature.

[219]  A. Verkhratsky,et al.  Glial Neurobiology: A Textbook , 2007 .

[220]  J. Rothstein,et al.  Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS , 2002, Annals of neurology.

[221]  S. Wesselingh,et al.  Correlation between neurological progression and astrocyte apoptosis in HIV‐associated dementia , 2001, Annals of neurology.

[222]  Miguel Maravall,et al.  The Barrel Cortex as a Model to Study Dynamic Neuroglial Interaction , 2009, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[223]  Y. Suh,et al.  C‐terminal fragment of amyloid precursor protein induces astrocytosis , 2001, Journal of neurochemistry.

[224]  G. Pasinetti,et al.  Potentiation of excitotoxicity in transgenic mice overexpressing neuronal cyclooxygenase-2. , 1999, The American journal of pathology.

[225]  H. Engler,et al.  Evidence for astrocytosis in ALS demonstrated by [11C](l)-deprenyl-D2 PET , 2007, Journal of the Neurological Sciences.

[226]  P. Mcgeer,et al.  Brain inflammation in Alzheimer disease and the therapeutic implications. , 1999, Current pharmaceutical design.

[227]  Kevin Eggan,et al.  Non–cell autonomous effect of glia on motor neurons in an embryonic stem cell–based ALS model , 2007, Nature Neuroscience.

[228]  T. Montine,et al.  Microglia Lacking E Prostanoid Receptor Subtype 2 Have Enhanced Aβ Phagocytosis yet Lack Aβ-Activated Neurotoxicity , 2005 .

[229]  Berislav V. Zlokovic,et al.  Neurovascular mechanisms and blood–brain barrier disorder in Alzheimer’s disease , 2009, Acta Neuropathologica.

[230]  Maiken Nedergaard,et al.  New roles for astrocytes (stars at last) , 2003, Trends in Neurosciences.

[231]  G. Carmignoto,et al.  Astrocyte control of synaptic transmission and neurovascular coupling. , 2006, Physiological reviews.

[232]  Julia W. Chang,et al.  Interleukin‐1β Induces Prostaglandin G/H Synthase‐2 (Cyclooxygenase‐2) in Primary Murine Astrocyte Cultures , 1996, Journal of neurochemistry.

[233]  K. Talbot,et al.  Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS , 2008, Progress in Neurobiology.

[234]  J. Parkinson An Essay on the Shaking Palsy , 2002 .

[235]  Scott Ferrell,et al.  Message and protein-level elevation of tumor necrosis factor α (TNFα) and TNFα-modulating cytokines in spinal cords of the G93A-SOD1 mouse model for amyotrophic lateral sclerosis , 2003, Neurobiology of Disease.

[236]  K. Frei,et al.  Production of macrophage colony-stimulating factor by astrocytes and brain macrophages , 1992, Journal of Neuroimmunology.

[237]  Y. Suh,et al.  α‐Synuclein induces migration of BV‐2 microglial cells by up‐regulation of CD44 and MT1‐MMP , 2009, Journal of neurochemistry.

[238]  B. Hyman,et al.  Microglial response to amyloid plaques in APPsw transgenic mice. , 1998, The American journal of pathology.

[239]  S. Wilks Lectures on Diseases of the Nervous System , 1885, Buffalo Medical and Surgical Journal.

[240]  R. Tanzi,et al.  Twenty Years of the Alzheimer’s Disease Amyloid Hypothesis: A Genetic Perspective , 2005, Cell.

[241]  C. Steinhäuser,et al.  Ion channels in glial cells , 2000, Brain Research Reviews.

[242]  T. Takadera,et al.  Prostaglandin E2 induced caspase-dependent apoptosis possibly through activation of EP2 receptors in cultured hippocampal neurons , 2004, Neurochemistry International.

[243]  Milos Pekny,et al.  Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury , 2006, Proceedings of the National Academy of Sciences.

[244]  R. North,et al.  Vesicular release of ATP at central synapses , 2006, Pflügers Archiv.

[245]  S. Goldman,et al.  New roles for astrocytes: Redefining the functional architecture of the brain , 2003, Trends in Neurosciences.

[246]  S. Narumiya,et al.  Prostanoid receptors: structures, properties, and functions. , 1999, Physiological reviews.

[247]  A Verkhratsky,et al.  Neuronismo y reticulismo: neuronal–glial circuits unify the reticular and neuronal theories of brain organization , 2009, Acta physiologica.

[248]  P. Mcgeer,et al.  Marked increase in cyclooxygenase-2 in ALS spinal cord , 2001, Neurology.

[249]  C. Giaume,et al.  Astrocyte calcium waves: What they are and what they do , 2006, Glia.

[250]  J. Dichgans,et al.  Protection by pioglitazone in the MPTP model of Parkinson's disease correlates with IκBα induction and block of NFκB and iNOS activation , 2003 .

[251]  M. C. Angulo,et al.  Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation , 2003, Nature Neuroscience.

[252]  Christian Steinhäuser,et al.  Astrocyte dysfunction in neurological disorders: a molecular perspective , 2006, Nature Reviews Neuroscience.

[253]  R. Mrak,et al.  Interleukin-1, neuroinflammation, and Alzheimer’s disease , 2001, Neurobiology of Aging.

[254]  A. Verkhratsky,et al.  Glial calcium: homeostasis and signaling function. , 1998, Physiological reviews.

[255]  F. Di Virgilio,et al.  Activation of Microglia by Amyloid β Requires P2X7 Receptor Expression1 , 2009, The Journal of Immunology.

[256]  Hynek Wichterle,et al.  Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons , 2007, Nature Neuroscience.

[257]  J. Julien,et al.  Minocycline Slows Disease Progression in a Mouse Model of Amyotrophic Lateral Sclerosis , 2002, Neurobiology of Disease.

[258]  Y. Chong Effect of a carboxy-terminal fragment of the Alzheimer's amyloid precursor protein on expression of proinflammatory cytokines in rat glial cells. , 1997, Life sciences.

[259]  M. Duchen,et al.  β-Amyloid Peptides Induce Mitochondrial Dysfunction and Oxidative Stress in Astrocytes and Death of Neurons through Activation of NADPH Oxidase , 2004, The Journal of Neuroscience.

[260]  L. Mucke,et al.  Prevention of HIV-1 gp120-induced neuronal damage in the central nervous system of transgenic mice by the NMDA receptor antagonist memantine , 1996, Brain Research.

[261]  E. Scarpini,et al.  Proinflammatory profile of cytokine production by human monocytes and murine microglia stimulated with β-amyloid[25–35] , 1999, Journal of Neuroimmunology.

[262]  D. Standaert,et al.  Targeted Overexpression of Human &agr;-Synuclein Triggers Microglial Activation and an Adaptive Immune Response in a Mouse Model of Parkinson Disease , 2008, Journal of neuropathology and experimental neurology.

[263]  L. Lue,et al.  Molecular and Cellular Characterization of the Membrane Attack Complex, C5b-9, in Alzheimer’s Disease , 1997, Neurobiology of Aging.

[264]  C. Wernicke,et al.  Lehrbuch der Gehirnkrankheiten für Aerzte und Studirende , 1881 .

[265]  Richard D. Kim,et al.  Reduced β-Amyloid Production and Increased Inflammatory Responses in Presenilin Conditional Knock-out Mice* , 2004, Journal of Biological Chemistry.

[266]  A. Lees The Parkinson chimera , 2009, Neurology.

[267]  A. Pérez-Samartín,et al.  Excitotoxic damage to white matter , 2007, Journal of anatomy.

[268]  S. Miller,et al.  Mechanisms of Immunopathology in Murine Models of Central Nervous System Demyelinating Disease1 , 2006, The Journal of Immunology.

[269]  F. Jessen,et al.  A genetic variation of the inflammatory cytokine interleukin‐6 delays the initial onset and reduces the risk for sporadic Alzheimer's disease , 1999, Annals of neurology.

[270]  R. Go,et al.  The role of TNF and its receptors in Alzheimer’s disease , 2001, Neurobiology of Aging.

[271]  L. Hersh,et al.  Insulin-degrading Enzyme Regulates Extracellular Levels of Amyloid β-Protein by Degradation* , 1998, The Journal of Biological Chemistry.

[272]  G. Perea,et al.  Tripartite synapses: astrocytes process and control synaptic information , 2009, Trends in Neurosciences.

[273]  K. Talbot,et al.  Motor neurone disease , 2002, Postgraduate medical journal.

[274]  B. Volpe,et al.  APP knockout attenuates microglial activation and enhances neuron survival in substantia nigra compacta after axotomy , 2002, Glia.

[275]  T. Montine,et al.  Microglial EP2 is critical to neurotoxicity from activated cerebral innate immunity , 2005, Glia.

[276]  F. Kirchhoff,et al.  NMDA Receptors in Glia , 2007, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[277]  J. Silver,et al.  Astrocytes Regulate Microglial Phagocytosis of Senile Plaque Cores of Alzheimer's Disease , 1998, Experimental Neurology.

[278]  G. Kollias,et al.  Onset and Progression in Inherited ALS Determined by Motor Neurons and Microglia , 2006, Science.

[279]  K. Hensley,et al.  Temporal patterns of cytokine and apoptosis‐related gene expression in spinal cords of the G93A‐SOD1 mouse model of amyotrophic lateral sclerosis , 2002 .

[280]  T. Komori,et al.  Tau‐positive dial Inclusions in Progressive Supranuclear Palsy, Corticobasal Degeneration and Pick's Disease , 1999, Brain pathology.

[281]  F. Haiss,et al.  Dynamics of the Microglial/Amyloid Interaction Indicate a Role in Plaque Maintenance , 2008, The Journal of Neuroscience.

[282]  B T Hyman,et al.  Chemokines/chemokine receptors in the central nervous system and Alzheimer's disease. , 1999, Journal of neurovirology.

[283]  R. Orkand,et al.  Modification of potassium movement through the retina of the drone (Apis mellifera male) by glial uptake. , 1983, The Journal of physiology.

[284]  P. Haydon,et al.  Astrocytic glutamate targets NMDA receptors , 2007, The Journal of physiology.

[285]  C. Giaume,et al.  Gap Junction-Mediated Astrocytic Networks in the Mouse Barrel Cortex , 2008, The Journal of Neuroscience.

[286]  D. Rampe,et al.  Amyloid-beta peptide fragments p3 and p4 induce pro-inflammatory cytokine and chemokine production in vitro and in vivo. , 2001, Journal of neurochemistry.

[287]  Todd A Fiacco,et al.  What Is the Role of Astrocyte Calcium in Neurophysiology? , 2008, Neuron.

[288]  Betty Y. S. Kim,et al.  Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice , 2002, Nature.

[289]  C. Weigert,et al.  Beiträge zur Kenntnis der normalen menschlichen Neuroglia , 1896 .

[290]  S. Mckercher,et al.  Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis , 2006, Proceedings of the National Academy of Sciences.

[291]  F. Pfrieger,et al.  Roles of glial cells in synapse development , 2009, Cellular and Molecular Life Sciences.

[292]  P. Mcgeer,et al.  Glial reactions in Parkinson's disease , 2008, Movement disorders : official journal of the Movement Disorder Society.

[293]  G. Sobue,et al.  Differential expression of inflammation‐ and apoptosis‐related genes in spinal cords of a mutant SOD1 transgenic mouse 
model of familial amyotrophic lateral sclerosis , 2002, Journal of neurochemistry.

[294]  L. McCullough,et al.  Neuroprotective Function of the PGE2 EP2 Receptor in Cerebral Ischemia , 2004, The Journal of Neuroscience.

[295]  P. Magistretti,et al.  Activity‐dependent regulation of energy metabolism by astrocytes: An update , 2007, Glia.

[296]  D. Holtzman,et al.  Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer’s disease , 2008, Nature.

[297]  H. Sontheimer,et al.  Spontaneous intracellular calcium oscillations in cortical astrocytes from a patient with intractable childhood epilepsy (Rasmussen's Encephalitis) , 1997, Glia.

[298]  P. Mcgeer,et al.  Distribution of cyclooxygenase-1 and cyclooxygenase-2 mRNAs and proteins in human brain and peripheral organs , 1999, Brain Research.

[299]  V. Nguyen,et al.  Immunological aspects of microglia: relevance to Alzheimer's disease , 2001, Neurochemistry International.

[300]  B. Hyman,et al.  Synchronous Hyperactivity and Intercellular Calcium Waves in Astrocytes in Alzheimer Mice , 2009, Science.

[301]  H. Arias,et al.  The role of inflammation in Alzheimer's disease. , 2005, The international journal of biochemistry & cell biology.

[302]  W. Gong,et al.  CpG‐containing oligodeoxynucleotide promotes microglial cell uptake of amyloid β 1–42 peptide by up‐regulating the expression of the G‐protein‐coupled receptor mFPR2 , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[303]  V. Perry,et al.  Microglial physiology: unique stimuli, specialized responses. , 2009, Annual review of immunology.

[304]  J. Trojanowski,et al.  Expression of the small heat-shock protein alphaB-crystallin in tauopathies with glial pathology. , 2004, The American journal of pathology.

[305]  Helmut Kettenmann,et al.  Calcium signalling in glial cells , 1996, Trends in Neurosciences.