Unregulated brain iron deposition in transgenic mice over-expressing HMOX1 in the astrocytic compartment

Authors

  • Wei Song,

    1. Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
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    • These authors contributed equally to this work.
  • Hillel Zukor,

    1. Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
    2. Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
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    • These authors contributed equally to this work.
  • Shih-Hsiung Lin,

    1. Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
    2. Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
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  • Adrienne Liberman,

    1. Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
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  • Ayda Tavitian,

    1. Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
    2. Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
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  • Jeannie Mui,

    1. Facility for Electron Microscopy Research, McGill University, Montreal, Quebec, Canada
    2. Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
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  • Hojatollah Vali,

    1. Facility for Electron Microscopy Research, McGill University, Montreal, Quebec, Canada
    2. Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
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  • Carine Fillebeen,

    1. Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
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  • Kostas Pantopoulos,

    1. Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
    2. Department of Medicine, McGill University, Montreal, Quebec, Canada
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  • Ting-Di Wu,

    1. INSERM, U759, Orsay, France
    2. Laboratoire de Microscopie Ionique, Institut Curie, Orsay, France
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  • Jean-Luc Guerquin-Kern,

    1. INSERM, U759, Orsay, France
    2. Laboratoire de Microscopie Ionique, Institut Curie, Orsay, France
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  • Hyman M. Schipper

    Corresponding author
    1. Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
    • Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
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Address correspondence and reprint requests to Hyman M. Schipper, Lady Davis Institute, Jewish General Hospital, 3755 Cote Ste. Catherine Road, Montreal, Quebec H3T 1E2, Canada.

E-mail: hyman.schipper@mcgill.ca

Abstract

The mechanisms responsible for pathological iron deposition in the aging and degenerating mammalian CNS remain poorly understood. The stress protein, HO-1 mediates the degradation of cellular heme to biliverdin/bilirubin, free iron, and CO and is up-regulated in the brains of persons with Alzheimer's disease and Parkinson's disease. HO-1 induction in primary astroglial cultures promotes deposition of non-transferrin iron, mitochondrial damage and macroautophagy, and predisposes cocultured neuronal elements to oxidative injury. To gain a better appreciation of the role of glial HO-1 in vivo, we probed for aberrant brain iron deposition using Perls' method and dynamic secondary ion mass spectrometry in novel, conditional GFAP.HMOX1 transgenic mice that selectively over-express human HO-1 in the astrocytic compartment. At 48 weeks, the GFAP.HMOX1 mice exhibited increased deposits of glial iron in hippocampus and other subcortical regions without overt changes in iron-regulatory and iron-binding proteins relative to age-matched wild-type animals. Dynamic secondary ion mass spectrometry revealed abundant FeO signals in the transgenic, but not wild-type, mouse brain that colocalized to degenerate mitochondria and osmiophilic cytoplasmic inclusions (macroautophagy) documented by TEM. Sustained up-regulation of HO-1 in astrocytes promotes pathological brain iron deposition and oxidative mitochondrial damage characteristic of Alzheimer's disease-affected neural tissues. Curtailment of glial HO-1 hyperactivity may limit iron-mediated cytotoxicity in aging and degenerating neural tissues.

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