Genetic ablation of Nrf2/antioxidant response pathway in Alexander disease mice reduces hippocampal gliosis but does not impact survival

PLoS One. 2012;7(5):e37304. doi: 10.1371/journal.pone.0037304. Epub 2012 May 31.


In Alexander disease (AxD) the presence of mutant glial fibrillary acidic protein (GFAP), the major intermediate filament of astrocytes, triggers protein aggregation, with marked induction of a stress response mediated by the transcription factor, Nrf2. To clarify the role of Nrf2 in AxD, we have crossed Gfap mutant and transgenic mouse models into an Nrf2 null background. Deletion of Nrf2 eliminates the phase II stress response normally present in mouse models of AxD, but causes no change in body weight or lifespan, even in a severe lethal model. AxD astrocytes without Nrf2 retain features of reactivity, such as expression of the endothelin-B receptor, but have lower Gfap levels, a decrease in p62 protein and reduced iron accumulation, particularly in hippocampus. Microglial activation, indicated by Iba1 expression, is also diminished. Although the Nrf2 response is generally considered beneficial, these results show that in the context of AxD, loss of the antioxidant pathway has no obvious negative effects, while actually decreasing Gfap accumulation and pathology. Given the attention Nrf2 is receiving as a potential therapeutic target in AxD and other neurodegenerative diseases, it will be interesting to see whether induction of Nrf2, beyond the endogenous response, is beneficial or not in these same models.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alexander Disease / genetics
  • Alexander Disease / metabolism*
  • Alexander Disease / pathology
  • Animals
  • Antioxidants / metabolism*
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Ceruloplasmin / metabolism
  • Down-Regulation / genetics
  • Ferritins / metabolism
  • Gene Deletion*
  • Gene Knockout Techniques
  • Glial Fibrillary Acidic Protein
  • Gliosis / genetics
  • Gliosis / metabolism*
  • Gliosis / pathology
  • Gliosis / physiopathology
  • Hippocampus / metabolism
  • Hippocampus / pathology*
  • Humans
  • Iron / metabolism
  • Mice
  • Microglia / metabolism
  • Microglia / pathology
  • NF-E2-Related Factor 2 / deficiency*
  • NF-E2-Related Factor 2 / genetics*
  • NF-E2-Related Factor 2 / metabolism
  • Nerve Tissue Proteins / metabolism
  • Stress, Physiological / genetics
  • Survival Analysis
  • Transcription Factor TFIIH
  • Transcription Factors / metabolism
  • alpha-Crystallin B Chain / metabolism


  • Antioxidants
  • Glial Fibrillary Acidic Protein
  • Gtf2h1 protein, mouse
  • NF-E2-Related Factor 2
  • Nerve Tissue Proteins
  • Transcription Factors
  • alpha-Crystallin B Chain
  • glial fibrillary astrocytic protein, mouse
  • Transcription Factor TFIIH
  • Ferritins
  • Iron
  • Ceruloplasmin