Unregulated brain iron deposition in transgenic mice over‐expressing HMOX1 in the astrocytic compartment
Identifieur interne : 000127 ( France/Analysis ); précédent : 000126; suivant : 000128Unregulated 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
Affiliations:
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Schipper</name><affiliation wicri:level="1"><country xml:lang="fr">Canada</country><wicri:regionArea>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec</wicri:regionArea><wicri:noRegion>Quebec</wicri:noRegion></affiliation><affiliation wicri:level="4"><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal</wicri:regionArea><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region><settlement type="city">Montréal</settlement></placeName><orgName type="university">Université McGill</orgName></affiliation><affiliation></affiliation><affiliation wicri:level="1"><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><affiliations><list><country><li>Canada</li><li>France</li></country><region><li>Québec</li></region><settlement><li>Montréal</li><li>Orsay</li></settlement><orgName><li>Université McGill</li></orgName></list><tree><country name="Canada"><region name="Québec"><name sortKey="Song, Wei" sort="Song, Wei" uniqKey="Song W" first="Wei" last="Song">Wei Song</name></region><name sortKey="Fillebeen, Carine" sort="Fillebeen, Carine" uniqKey="Fillebeen C" first="Carine" last="Fillebeen">Carine Fillebeen</name><name sortKey="Liberman, Adrienne" sort="Liberman, Adrienne" uniqKey="Liberman A" first="Adrienne" last="Liberman">Adrienne Liberman</name><name sortKey="Lin, Shih Siung" sort="Lin, Shih Siung" uniqKey="Lin S" first="Shih-Hsiung" last="Lin">Shih-Hsiung Lin</name><name sortKey="Lin, Shih Siung" sort="Lin, Shih Siung" uniqKey="Lin S" first="Shih-Hsiung" last="Lin">Shih-Hsiung Lin</name><name sortKey="Mui, Jeannie" sort="Mui, Jeannie" uniqKey="Mui J" first="Jeannie" last="Mui">Jeannie Mui</name><name sortKey="Mui, Jeannie" sort="Mui, Jeannie" uniqKey="Mui J" first="Jeannie" last="Mui">Jeannie Mui</name><name sortKey="Pantopoulos, Kostas" sort="Pantopoulos, Kostas" uniqKey="Pantopoulos K" first="Kostas" last="Pantopoulos">Kostas Pantopoulos</name><name sortKey="Pantopoulos, Kostas" sort="Pantopoulos, Kostas" uniqKey="Pantopoulos K" first="Kostas" last="Pantopoulos">Kostas Pantopoulos</name><name sortKey="Schipper, Hyman M" sort="Schipper, Hyman M" uniqKey="Schipper H" first="Hyman M." last="Schipper">Hyman M. Schipper</name><name sortKey="Schipper, Hyman M" sort="Schipper, Hyman M" uniqKey="Schipper H" first="Hyman M." last="Schipper">Hyman M. Schipper</name><name sortKey="Schipper, Hyman M" sort="Schipper, Hyman M" uniqKey="Schipper H" first="Hyman M." last="Schipper">Hyman M. Schipper</name><name sortKey="Tavitian, Ayda" sort="Tavitian, Ayda" uniqKey="Tavitian A" first="Ayda" last="Tavitian">Ayda Tavitian</name><name sortKey="Tavitian, Ayda" sort="Tavitian, Ayda" uniqKey="Tavitian A" first="Ayda" last="Tavitian">Ayda Tavitian</name><name sortKey="Vali, Hojatollah" sort="Vali, Hojatollah" uniqKey="Vali H" first="Hojatollah" last="Vali">Hojatollah Vali</name><name sortKey="Vali, Hojatollah" sort="Vali, Hojatollah" uniqKey="Vali H" first="Hojatollah" last="Vali">Hojatollah Vali</name><name sortKey="Zukor, Hillel" sort="Zukor, Hillel" uniqKey="Zukor H" first="Hillel" last="Zukor">Hillel Zukor</name><name sortKey="Zukor, Hillel" sort="Zukor, Hillel" uniqKey="Zukor H" first="Hillel" last="Zukor">Hillel Zukor</name></country><country name="France"><noRegion><name sortKey="Wu, Ting I" sort="Wu, Ting I" uniqKey="Wu T" first="Ting-Di" last="Wu">Ting-Di Wu</name></noRegion><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><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><name sortKey="Wu, Ting I" sort="Wu, Ting I" uniqKey="Wu T" first="Ting-Di" last="Wu">Ting-Di Wu</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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