Mechanisms of Disease: astrocytes in neurodegenerative disease

The term neurodegenerative disease refers to the principal pathology associated with disorders such as amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease and Parkinson's disease, and it is presumed that neurodegeneration results in the clinical findings seen in patients with these diseases. Decades of pathological and physiological studies have focused on neuronal abnormalities in these disorders, but it is becoming increasingly evident that astrocytes are also important players in these and other neurological disorders. Our understanding of the normative biology of astrocytes has been aided by the development of animal models in which astrocyte-specific proteins and pathways have been manipulated, and mouse models of neurodegenerative diseases have also revealed astrocyte-specific pathologies that contribute to neurodegeneration. These models have led to the development of targeted therapies for pathways in which astrocytes participate, and this research should ultimately influence the clinical treatment of neurodegenerative disorders.

[1]  P. Burnett,et al.  Calcium oscillations in type-1 astrocytes, the effect of a presenilin 1 (PS1) mutation , 2006, Neuroscience Letters.

[2]  J. Storm-Mathisen,et al.  Glutamate transporters in glial plasma membranes: Highly differentiated localizations revealed by quantitative ultrastructural immunocytochemistry , 1995, Neuron.

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

[4]  K. Lindenberg,et al.  Impaired glutamate transport and glutamate-glutamine cycling: downstream effects of the Huntington mutation. , 2002, Brain : a journal of neurology.

[5]  C. Brenner.  Genomic approaches to elucidation of the Fhit pathway in worms and yeast: Rosetta Stone and synthetic lethals , 2001, Nature Genetics.

[6]  Minh N. H. Nguyen,et al.  Wild-Type Nonneuronal Cells Extend Survival of SOD1 Mutant Motor Neurons in ALS Mice , 2003, Science.

[7]  M. Pekny,et al.  Astrocytic intermediate filaments: lessons from GFAP and vimentin knock-out mice. , 2001, Progress in brain research.

[8]  R. Dermietzel,et al.  Gap junctions between cultured astrocytes: immunocytochemical, molecular, and electrophysiological analysis , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[9]  Timothy A. Miller,et al.  Virus‐delivered small RNA silencing sustains strength in amyotrophic lateral sclerosis , 2005, Annals of neurology.

[10]  Ji-Yeon Shin,et al.  Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity , 2005, The Journal of cell biology.

[11]  J. Trojanowski,et al.  Impaired Glutamate Transport in a Mouse Model of Tau Pathology in Astrocytes , 2006, The Journal of Neuroscience.

[12]  Y. L. Lee,et al.  Astrocytes cultured from transgenic mice carrying the added human glial fibrillary acidic protein gene contain rosenthal fibers , 1998, Journal of neuroscience research.

[13]  B L Langille,et al.  Cardiac malformation in neonatal mice lacking connexin43. , 1995, Science.

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

[15]  Georg Grön,et al.  The RNA of the glutamate transporter EAAT2 is variably spliced in amyotrophic lateral sclerosis and normal individuals , 1999, Journal of the Neurological Sciences.

[16]  J. Storm-Mathisen,et al.  Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[17]  S. Hayashi,et al.  NACP/α-synuclein-positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson’s disease brains , 2000, Acta Neuropathologica.

[18]  D. Rodriguez,et al.  Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease , 2001, Nature Genetics.

[19]  A. Mahal,et al.  Impaired Glutamate Uptake in the R6 Huntington's Disease Transgenic Mice , 2001, Neurobiology of Disease.

[20]  G. Donowitz,et al.  Beta-Lactam Antibiotics , 1988 .

[21]  V. Hachinski,et al.  Connexin43 null mutation increases infarct size after stroke , 2001, The Journal of comparative neurology.

[22]  A. Levey,et al.  Localization of neuronal and glial glutamate transporters , 1994, Neuron.

[23]  J. Rothstein,et al.  Glutamate transporter gene expression in amyotrophic lateral sclerosis motor cortex , 1996, Annals of neurology.

[24]  N. Danbolt.  Glutamate uptake , 2001, Progress in Neurobiology.

[25]  J. Rothstein,et al.  Glutamate transporters: animal models to neurologic disease , 2004, Neurobiology of Disease.

[26]  D. Borchelt,et al.  ALS-Linked SOD1 Mutant G85R Mediates Damage to Astrocytes and Promotes Rapidly Progressive Disease with SOD1-Containing Inclusions , 1997, Neuron.

[27]  P. Haydon.  Glia: listening and talking to the synapse , 2001, Nature Reviews Neuroscience.

[28]  Hajime Hirase,et al.  A multi-photon window onto neuronal–glial–vascular communication , 2005, Trends in Neurosciences.

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

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

[31]  Mark P. Mattson,et al.  Alzheimer’s amyloid β-peptide enhances ATP/gap junction-mediated calcium-wave propagation in astrocytes , 2007, NeuroMolecular Medicine.

[32]  J. Wegiel,et al.  Spatial relationships between astrocytes and classical plaque components , 1991, Neurobiology of Aging.

[33]  D W Dickson,et al.  Widespread cytoskeletal pathology characterizes corticobasal degeneration. , 1995, The American journal of pathology.

[34]  John G. Nutt,et al.  Diagnosis and Initial Management of Parkinson's Disease , 2005 .

[35]  D. Selkoe.  Alzheimer's disease: genes, proteins, and therapy. , 2001, Physiological reviews.

[36]  B. Banwell,et al.  Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease , 2005, Annals of neurology.

[37]  S. Patel,et al.  Amyotrophic Lateral Sclerosis: Pathogenesis, Differential Diagnoses, And Potential Interventions , 2002, The journal of spinal cord medicine.

[38]  H. Suwaki,et al.  Amygdala-kindled and pentylenetetrazole-induced seizures in glutamate transporter GLAST-deficient mice , 1999, Brain Research.

[39]  John G Nutt,et al.  Clinical practice. Diagnosis and initial management of Parkinson's disease. , 2005, The New England journal of medicine.

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

[41]  B. Ransom,et al.  Functional Hemichannels in Astrocytes: A Novel Mechanism of Glutamate Release , 2003, The Journal of Neuroscience.

[42]  L. Greensmith,et al.  Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model , 2005, Nature Medicine.

[43]  E. Freye.  Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1 , 1997 .

[44]  A. Mitani,et al.  Functional Changes of Glial Glutamate Transporter GLT-1 during Ischemia: An In Vivo Study in the Hippocampal CA1 of Normal Mice and Mutant Mice Lacking GLT-1 , 2003, The Journal of Neuroscience.

[45]  A Weindl,et al.  Changes of NMDA Receptor Subunit (NR1, NR2B) and Glutamate Transporter (GLT1) mRNA Expression in Huntington's Disease—An In Situ Hybridization Study , 1997, Journal of neuropathology and experimental neurology.

[46]  Lin Jin,et al.  Aberrant RNA Processing in a Neurodegenerative Disease: the Cause for Absent EAAT2, a Glutamate Transporter, in Amyotrophic Lateral Sclerosis , 1998, Neuron.

[47]  D. Price,et al.  Histological Evidence of Protein Aggregation in Mutant SOD1 Transgenic Mice and in Amyotrophic Lateral Sclerosis Neural Tissues , 2001, Neurobiology of Disease.

[48]  E. Tolosa,et al.  Intranigral infusion of interleukin‐1β activates astrocytes and protects from subsequent 6‐hydroxydopamine neurotoxicity , 2003, Journal of neurochemistry.

[49]  P. Ince,et al.  Expression of the glial glutamate transporter EAAT2 in the human CNS: an immunohistochemical study. , 1997, Brain research. Molecular brain research.

[50]  P. Fisher,et al.  β-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression , 2005, Nature.

[51]  J. Langston,et al.  Astrocytes and Parkinson's disease. , 1992, Progress in brain research.

[52]  J. Powell,et al.  Intron 7 retention and exon 9 skipping EAAT2 mRNA variants are not associated with amyotrophic lateral sclerosis , 2001, Annals of neurology.

[53]  J. Langston,et al.  Chapter 36: Astrocytes and Parkinson's disease , 1992 .

[54]  J. Schulz,et al.  Cellular pathology of Parkinson’s disease: astrocytes, microglia and inflammation , 2004, Cell and Tissue Research.

[55]  M. Sofroniew,et al.  Reactive Astrocytes in Neural Repair and Protection , 2005, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

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

[57]  D. Borchelt,et al.  An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria , 1995, Neuron.

[58]  Mark Ellisman,et al.  Absence of Glial Fibrillary Acidic Protein and Vimentin Prevents Hypertrophy of Astrocytic Processes and Improves Post-Traumatic Regeneration , 2004, The Journal of Neuroscience.

[59]  S. Paul,et al.  Microglial apolipoprotein E and astroglial apolipoprotein J expression in vitro: opposite effects of lipopolysaccharide , 2003, Journal of neurochemistry.

[60]  M. Hediger,et al.  Knockout of Glutamate Transporters Reveals a Major Role for Astroglial Transport in Excitotoxicity and Clearance of Glutamate , 1996, Neuron.

[61]  N. Severs,et al.  CONNEXIN EXPRESSION IN HUNTINGTON'S DISEASED HUMAN BRAIN , 1998, Cell biology international.

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

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

[64]  O. Hurtado,et al.  A polymorphism in the EAAT2 promoter is associated with higher glutamate concentrations and higher frequency of progressing stroke , 2006, The Journal of experimental medicine.

[65]  G. Bishop,et al.  Increased expression of the glial glutamate transporter EAAT2 modulates excitotoxicity and delays the onset but not the outcome of ALS in mice. , 2003, Human molecular genetics.

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

[67]  S. Heales,et al.  Neurodegeneration or Neuroprotection: The Pivotal Role of Astrocytes , 2004, Neurochemical Research.

[68]  J. Wood,et al.  Huntingtin Protein Colocalizes with Lesions of Neurodegenerative Diseases: An Investigation in Huntington's, Alzheimer's, and Pick's Diseases , 1998, Experimental Neurology.

[69]  J. Rothstein,et al.  Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS) , 2002, Proceedings of the National Academy of Sciences of the United States of America.

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

[71]  E. Hirsch,et al.  Glutathione peroxidase, glial cells and Parkinson's disease , 1993, Neuroscience.

[72]  J. Rothstein,et al.  Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. , 1992, The New England journal of medicine.