Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mechanisms of Disease: astrocytes in neurodegenerative disease

Abstract

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.

Key Points

  • Astrocytes perform critical roles in amino acid, nutrient and ion metabolism in the brain, coupling of neuronal activity and cerebral blood flow, and modulation of excitatory synaptic transmission

  • Transgenic and knockout mouse models of astrocyte-specific proteins have demonstrated that astrocytes play a role in both neuroprotection and neurodegeneration, particularly following an insult

  • Selective expression of mutant proteins associated with neurodegenerative diseases in astrocytes is sufficient to cause neuronal damage

  • Mutations in the astrocyte-specific intermediate filament protein glial fibrillary acidic protein is associated with the neurodegenerative disorder Alexander disease

  • Astrocytes might be particularly attractive—and underappreciated—targets for neurodegenerative disease therapeutics

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Normal functions of astrocytes.
Figure 2: Potential astrocyte dysfunction in neurodegenerative diseases.

References

  1. Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65: 1–105

    Article  CAS  Google Scholar 

  2. Kofuji P and Newman EA (2004) Potassium buffering in the central nervous system. Neuroscience 129: 1045–1056

    Article  CAS  Google Scholar 

  3. Hirase H (2005) A multi-photon window onto neuronal-glial-vascular communication. Trends Neurosci 28: 217–219

    Article  CAS  Google Scholar 

  4. Takano T et al. (2006) Astrocyte-mediated control of cerebral blood flow. Nat Neurosci 9: 260–267

    Article  CAS  Google Scholar 

  5. Chaudhry FA et al. (1995) Glutamate transporters in glial plasma membranes: highly differentiated localizations revealed by quantitative ultrastructural immunocytochemistry. Neuron 15: 711–720

    Article  CAS  Google Scholar 

  6. Lehre KP et al. (1995) Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations. J Neurosci 15: 1835–1853

    Article  CAS  Google Scholar 

  7. Milton ID et al. (1997) Expression of the glial glutamate transporter EAAT2 in the human CNS: an immunohistochemical study. Mol Brain Res 52: 17–31

    Article  CAS  Google Scholar 

  8. Rothstein JD et al. (1994) Localization of neuronal and glial glutamate transporters. Neuron 13: 713–725

    Article  CAS  Google Scholar 

  9. Rothstein JD et al. (1996) Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16: 675–686

    Article  CAS  Google Scholar 

  10. Tanaka K et al. (1997) Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276: 1699–1702

    Article  CAS  Google Scholar 

  11. Bezzi P et al. (2001) CXCR4-activated astrocyte glutamate release via TNFα: amplification by microglia triggers neurotoxicity. Nat Neurosci 4: 702–710

    Article  CAS  Google Scholar 

  12. Haydon PG (2001) Glia: listening and talking to the synapse. Nat Rev Neurosci 2: 185–193

    Article  CAS  Google Scholar 

  13. Ye ZC et al. (2003) Functional hemichannels in astrocytes: a novel mechanism of glutamate release. J Neurosci 23: 3588–3596

    Article  CAS  Google Scholar 

  14. Simard M and Nedergaard M (2004) The neurobiology of glia in the context of water and ion homeostasis. Neuroscience 129: 877–896

    Article  CAS  Google Scholar 

  15. Pekny M (2001) Astrocytic intermediate filaments: lessons from GFAP and vimentin knock-out mice. Prog Brain Res 132: 23–30

    Article  CAS  Google Scholar 

  16. Eng LF et al. (1998) Astrocytes cultured from transgenic mice carrying the added human glial fibrillary acidic protein gene contain Rosenthal fibers. J Neurosci Res 53: 353–360

    Article  CAS  Google Scholar 

  17. Wilhelmsson U et al. (2004) Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration. J Neurosci 24: 5016–5021

    Article  CAS  Google Scholar 

  18. Tanaka K et al. (1997) Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276: 1699–1702

    Article  CAS  Google Scholar 

  19. Mitani A and Tanaka K (2003) 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. J Neurosci 23: 7176–7182

    Article  CAS  Google Scholar 

  20. Watanabe T et al. (1999) Amygdala-kindled and pentylenetetrazole-induced seizures in glutamate transporter GLAST-deficient mice. Brain Res 845: 92–96

    Article  CAS  Google Scholar 

  21. Mallolas J et al. (2006) A polymorphism in the EAAT2 promoter is associated with higher glutamate concentrations and higher frequency of progressing stroke. J Exp Med 203: 711–717

    Article  CAS  Google Scholar 

  22. Sofroniew MV (2005) Reactive astrocytes in neural repair and protection. Neuroscientist 11: 400–407

    Article  CAS  Google Scholar 

  23. Dermietzel R et al. (1991) Gap junctions between cultured astrocytes: immunocytochemical, molecular, and electrophysiological analysis. J Neurosci 11: 1421–1432

    Article  CAS  Google Scholar 

  24. Reaume AG et al. (1995) Cardiac malformation in neonatal mice lacking connexin43. Science 267: 1831–1834

    Article  CAS  Google Scholar 

  25. Siushansian R et al. (2001) Connexin43 null mutation increases infarct size after stroke. J Comp Neurol 440: 387–394

    Article  CAS  Google Scholar 

  26. Patel SA and Maragakis NJ (2002) Amyotrophic lateral sclerosis: pathogenesis, differential diagnoses, and potential interventions. J Spinal Cord Med 25: 262–273

    Article  Google Scholar 

  27. Bristol LA and Rothstein JD (1996) Glutamate transporter gene expression in amyotrophic lateral sclerosis motor cortex. Ann Neurol 39: 676–679

    Article  CAS  Google Scholar 

  28. Lin CL et al. (1998) Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis. Neuron 20: 589–602

    Article  CAS  Google Scholar 

  29. Meyer T et al. (1999) The RNA of the glutamate transporter EAAT2 is variably spliced in amyotrophic lateral sclerosis and normal individuals. J Neurol Sci 170: 45–50

    Article  CAS  Google Scholar 

  30. Flowers JM et al. (2001) Intron 7 retention and exon 9 skipping EAAT2 mRNA variants are not associated with amyotrophic lateral sclerosis. Ann Neurol 49: 643–649

    Article  CAS  Google Scholar 

  31. Gurney ME et al. (1994) Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264: 1772–1775

    Article  CAS  Google Scholar 

  32. Wong PC et al. (1995) An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14: 1105–1116

    Article  CAS  Google Scholar 

  33. Bruijn LI et al. (1997) ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18: 327–338

    Article  CAS  Google Scholar 

  34. Howland DS et al. (2002) Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci USA 99: 1604–1609

    Article  CAS  Google Scholar 

  35. Guo H et al. (2003) Increased expression of the glial glutamate transporter EAAT2 modulates excitotoxicity and delays the onset but not the outcome of ALS in mice. Hum Mol Genet 12: 2519–2532

    Article  CAS  Google Scholar 

  36. Clement AM et al. (2003) Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302: 113–117

    Article  CAS  Google Scholar 

  37. Miller TM et al. (2005) Virus-delivered small RNA silencing sustains strength in amyotrophic lateral sclerosis. Ann Neurol 57: 773–776

    Article  CAS  Google Scholar 

  38. Ralph GS et al. (2005) Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model. Nat Med 11: 429–433

    Article  CAS  Google Scholar 

  39. Selkoe DJ (2001) Alzheimer's disease: genes, proteins, and therapy. Physiol Rev 81: 741–766

    Article  CAS  Google Scholar 

  40. Wisniewski HM and Wegiel J (1991) Spatial relationships between astrocytes and classical plaque components. Neurobiol Aging 12: 593–600

    Article  CAS  Google Scholar 

  41. DeWitt DA et al. (1998) Astrocytes regulate microglial phagocytosis of senile plaque cores of Alzheimer's disease. Exp Neurol 149: 329–340

    Article  CAS  Google Scholar 

  42. Nagele RG et al. (2004) Contribution of glial cells to the development of amyloid plaques in Alzheimer's disease. Neurobiol Aging 25: 663–674

    Article  CAS  Google Scholar 

  43. Haughey NJ and Mattson MP (2003) Alzheimer's amyloid beta-peptide enhances ATP/gap junction-mediated calcium-wave propagation in astrocytes. Neuromolecular Med 3: 173–180

    Article  Google Scholar 

  44. Johnston JM et al. (2006) Calcium oscillations in type-1 astrocytes, the effect of a presenilin 1 (PS1) mutation. Neurosci Lett 395: 159–164

    Article  CAS  Google Scholar 

  45. Feany MB and Dickson DW (1995) Widespread cytoskeletal pathology characterizes corticobasal degeneration. Am J Pathol 146: 1388–1396

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Komori T (1999) Tau-positive glial inclusions in progressive supranuclear palsy, corticobasal degeneration and Pick's disease. Brain Pathol 9: 663–679

    Article  CAS  Google Scholar 

  47. Forman MS et al. (2005) Transgenic mouse model of tau pathology in astrocytes leading to nervous system degeneration. J Neurosci 25: 3539–3550

    Article  CAS  Google Scholar 

  48. Dabir DV et al. (2006) Impaired glutamate transport in a mouse model of tau pathology in astrocytes. J Neurosci 26: 644–654

    Article  CAS  Google Scholar 

  49. Hersch SM et al. (2004) In Neurologic Principles and Practice, 503–526 (Ed Koller W) New York: McGraw-Hill

    Google Scholar 

  50. Singhrao SK et al. (1998) Huntingtin protein colocalizes with lesions of neurodegenerative diseases: an investigation in Huntington's, Alzheimer's, and Pick's diseases. Exp Neurol 150: 213–222

    Article  CAS  Google Scholar 

  51. Arzberger T et al. (1997) Changes of NMDA receptor subunit (NR1, NR2B) and glutamate transporter (GLT1) mRNA expression in Huntington's disease—an in situ hybridization study. J Neuropathol Exp Neurol 56: 440–454

    Article  CAS  Google Scholar 

  52. Rothstein JD et al. (1992) Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 326: 1464–1468

    Article  CAS  Google Scholar 

  53. Vis JC et al. (1998) Connexin expression in Huntington's diseased human brain. Cell Biol Int 22: 837–847

    Article  CAS  Google Scholar 

  54. Lievens JC et al. (2001) Impaired glutamate uptake in the R6 Huntington's disease transgenic mice. Neurobiol Dis 8: 807–821

    Article  CAS  Google Scholar 

  55. Behrens PF et al. (2002) Impaired glutamate transport and glutamate-glutamine cycling: downstream effects of the Huntington mutation. Brain 125: 1908–1922

    Article  CAS  Google Scholar 

  56. Shin JY et al. (2005) Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity. J Cell Biol 171: 1001–1012

    Article  CAS  Google Scholar 

  57. Nutt JG and Wooten GF (2005) Clinical practice: diagnosis and initial management of Parkinson's disease. N Engl J Med 353: 1021–1027

    Article  CAS  Google Scholar 

  58. Forno LS et al. (1992) Astrocytes and Parkinson's disease. Prog Brain Res 94: 429–436

    Article  CAS  Google Scholar 

  59. Damier P et al. (1993) Glutathione peroxidase, glial cells and Parkinson's disease. Neuroscience 52: 1–6

    Article  CAS  Google Scholar 

  60. Wakabayashi K et al. (2000) NACP/α-synuclein-positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson's disease brains. Acta Neuropathol (Berl) 99: 14–20

    Article  CAS  Google Scholar 

  61. Teismann P and Schulz JB (2004) Cellular pathology of Parkinson's disease: astrocytes, microglia and inflammation. Cell Tissue Res 318: 149–161

    Article  Google Scholar 

  62. Saura J et al. (2003) Intranigral infusion of interleukin-1beta activates astrocytes and protects from subsequent 6-hydroxydopamine neurotoxicity. J Neurochem 85: 651–661

    Article  CAS  Google Scholar 

  63. Heales SJ et al. (2004) Neurodegeneration or neuroprotection: the pivotal role of astrocytes. Neurochem Res 29: 513–519

    Article  CAS  Google Scholar 

  64. Maragakis NJ and Rothstein JD (2004) Glutamate transporters: animal models to neurologic disease. Neurobiol Dis 15: 461–473

    Article  CAS  Google Scholar 

  65. Brenner M et al. (2001) Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet 27: 117–120

    Article  CAS  Google Scholar 

  66. Li R et al. (2005) Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease. Ann Neurol 57: 310–326

    Article  Google Scholar 

  67. Rothstein JD et al. (2005) Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433: 73–77

    Article  CAS  Google Scholar 

  68. Watanabe M et al. (2001) Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues. Neurobiol Dis 8: 933–941

    Article  CAS  Google Scholar 

Download references

Author information

Authors

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Maragakis, N., Rothstein, J. Mechanisms of Disease: astrocytes in neurodegenerative disease. Nat Rev Neurol 2, 679–689 (2006). https://doi.org/10.1038/ncpneuro0355

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpneuro0355

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing