Unregulated brain iron deposition in transgenic mice over‐expressing HMOX1 in the astrocytic compartment
Identifieur interne : 001A01 ( Istex/Curation ); précédent : 001A00; suivant : 001A02Unregulated brain iron deposition in transgenic mice over‐expressing HMOX1 in the astrocytic compartment
Auteurs : Wei Song [Canada] ; Hillel Zukor [Canada] ; Shih-Hsiung Lin [Canada] ; Adrienne Liberman [Canada] ; Ayda Tavitian [Canada] ; Jeannie Mui [Canada] ; Hojatollah Vali [Canada] ; Carine Fillebeen [Canada] ; Kostas Pantopoulos [Canada] ; Ting-Di Wu [France] ; Jean-Luc Guerquin-Kern [France] ; Hyman M. Schipper [Canada]Source :
- Journal of Neurochemistry [ 0022-3042 ] ; 2012-10.
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.
Url:
DOI: 10.1111/j.1471-4159.2012.07914.x
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transgenic mice over‐expressing HMOX1 in the astrocytic compartment</title><author><name sortKey="Song, Wei" sort="Song, Wei" uniqKey="Song W" first="Wei" last="Song">Wei Song</name><affiliation wicri:level="1"><mods:affiliation>Lady Davis Institute, Jewish General Hospital, Quebec, Montreal, Canada</mods:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Lady Davis Institute, Jewish General Hospital, Quebec, Montreal</wicri:regionArea></affiliation></author><author><name sortKey="Zukor, Hillel" sort="Zukor, Hillel" uniqKey="Zukor H" first="Hillel" last="Zukor">Hillel Zukor</name><affiliation wicri:level="1"><mods:affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</mods:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</mods:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal</wicri:regionArea></affiliation></author><author><name sortKey="Lin, Shih Siung" sort="Lin, Shih Siung" uniqKey="Lin S" first="Shih-Hsiung" last="Lin">Shih-Hsiung Lin</name><affiliation wicri:level="1"><mods:affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</mods:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</mods:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal</wicri:regionArea></affiliation></author><author><name 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Canada</mods:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal</wicri:regionArea></affiliation></author><author><name sortKey="Mui, Jeannie" sort="Mui, Jeannie" uniqKey="Mui J" first="Jeannie" last="Mui">Jeannie Mui</name><affiliation wicri:level="1"><mods:affiliation>Facility for Electron Microscopy Research, McGill University, Montreal, Quebec, Canada</mods:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Facility for Electron Microscopy Research, McGill University, Montreal, Quebec</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Quebec, Montreal, Canada</mods:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Quebec, Montreal</wicri:regionArea></affiliation></author><author><name sortKey="Vali, Hojatollah" sort="Vali, Hojatollah" uniqKey="Vali H" first="Hojatollah" last="Vali">Hojatollah Vali</name><affiliation wicri:level="1"><mods:affiliation>Facility for Electron Microscopy Research, McGill University, Montreal, Quebec, Canada</mods:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Facility for Electron Microscopy Research, McGill University, Montreal, Quebec</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Quebec, Montreal, Canada</mods:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Quebec, Montreal</wicri:regionArea></affiliation></author><author><name sortKey="Fillebeen, Carine" sort="Fillebeen, Carine" uniqKey="Fillebeen C" first="Carine" last="Fillebeen">Carine Fillebeen</name><affiliation wicri:level="1"><mods:affiliation>Lady Davis Institute, Jewish General Hospital, Quebec, Montreal, Canada</mods:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Lady Davis Institute, Jewish General Hospital, Quebec, Montreal</wicri:regionArea></affiliation></author><author><name sortKey="Pantopoulos, Kostas" sort="Pantopoulos, Kostas" uniqKey="Pantopoulos K" first="Kostas" last="Pantopoulos">Kostas Pantopoulos</name><affiliation wicri:level="1"><mods:affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</mods:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>Department of Medicine, McGill University, Quebec, Montreal, Canada</mods:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medicine, McGill University, Quebec, Montreal</wicri:regionArea></affiliation></author><author><name sortKey="Wu, Ting I" sort="Wu, Ting I" uniqKey="Wu T" first="Ting-Di" last="Wu">Ting-Di Wu</name><affiliation wicri:level="1"><mods:affiliation>INSERM, U759, Orsay, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>INSERM, U759, Orsay</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>Laboratoire de Microscopie Ionique, Institut Curie, Orsay, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Laboratoire de Microscopie Ionique, Institut Curie, Orsay</wicri:regionArea></affiliation></author><author><name sortKey="Guerquin Ern, Jean Uc" sort="Guerquin Ern, Jean Uc" uniqKey="Guerquin Ern J" first="Jean-Luc" last="Guerquin-Kern">Jean-Luc Guerquin-Kern</name><affiliation wicri:level="1"><mods:affiliation>INSERM, U759, Orsay, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>INSERM, U759, Orsay</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>Laboratoire de Microscopie Ionique, Institut Curie, Orsay, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Laboratoire de Microscopie Ionique, Institut Curie, Orsay</wicri:regionArea></affiliation></author><author><name sortKey="Schipper, Hyman M" sort="Schipper, Hyman M" uniqKey="Schipper H" first="Hyman M." last="Schipper">Hyman M. Schipper</name><affiliation wicri:level="1"><mods:affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</mods:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</mods:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal</wicri:regionArea></affiliation><affiliation><mods:affiliation>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:</mods:affiliation></affiliation><affiliation wicri:level="1"><mods:affiliation>E-mail: hyman.schipper@mcgill.ca</mods:affiliation><country wicri:rule="url">Canada</country></affiliation></author></analytic><monogr></monogr><series><title level="j">Journal of Neurochemistry</title><title level="j" type="abbrev">J. Neurochem.</title><idno type="ISSN">0022-3042</idno><idno type="eISSN">1471-4159</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><date type="published" when="2012-10">2012-10</date><biblScope unit="volume">123</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="325">325</biblScope><biblScope unit="page" to="336">336</biblScope></imprint><idno type="ISSN">0022-3042</idno></series><idno type="istex">F0D5E4339A4E31F36CA2940BEFAE38B0561B7008</idno><idno type="DOI">10.1111/j.1471-4159.2012.07914.x</idno><idno type="ArticleID">JNC7914</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-3042</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="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.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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