Alexander disease: putative mechanisms of an astrocytic encephalopathy

Cell Mol Life Sci. 2004 Feb;61(3):369-85. doi: 10.1007/s00018-003-3143-3.


Alexander disease (AXD) is the first primary astrocytic disorder. This encephalopathy is caused by dominant mutations in the glial fibrillary acidic protein (GFAP) gene, encoding the main intermediate filament of astrocyte. Pathologically, this neurodegenerative disease is characterised by dystrophic astrocytes containing intermediate filament aggregates associated with myelin abnormalities. More than 20 GFAP mutations have been reported. Many of them cluster in highly conserved regions between several intermediate filaments. Contrary to other intermediate filament-related diseases, AXD seems to be the consequence of a toxic gain of function induced by aggregates. This is supported by the phenotype of mice overexpressing human GFAP. Nevertheless, GFAP null mice display myelin abnormalities and blood-brain barrier dysfunction that are present in AXD. Given the pivotal role of astrocytes in brain physiology, there are many possibilities for astrocytes to dysfunction and to impair the functions of other cells. Physiopathological hypotheses are discussed in the frame of AXD.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alexander Disease / genetics*
  • Alexander Disease / pathology
  • Alexander Disease / physiopathology*
  • Amino Acid Sequence
  • Animals
  • Astrocytes / physiology
  • Blood-Brain Barrier
  • Brain / metabolism
  • Brain / pathology
  • Disease Models, Animal
  • Genome, Human*
  • Glial Fibrillary Acidic Protein / genetics
  • Glial Fibrillary Acidic Protein / metabolism
  • Glutamic Acid / metabolism
  • Humans
  • Molecular Sequence Data
  • Sequence Alignment


  • Glial Fibrillary Acidic Protein
  • Glutamic Acid