title: Unregulated brain iron deposition in transgenic mice over-expressing HMOX1 in the astrocytic compartment.
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.
authors.affiliation: Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.forename: Hillel
authors.initials: H
authors.lastname: Zukor
authors.forename: Shih-Hsiung
authors.initials: SH
authors.lastname: Lin
authors.forename: Adrienne
authors.initials: A
authors.lastname: Liberman
authors.forename: Ayda
authors.initials: A
authors.lastname: Tavitian
authors.forename: Jeannie
authors.initials: J
authors.lastname: Mui
authors.forename: Hojatollah
authors.initials: H
authors.lastname: Vali
authors.forename: Carine
authors.initials: C
authors.lastname: Fillebeen
authors.forename: Kostas
authors.initials: K
authors.lastname: Pantopoulos
authors.forename: Ting-Di
authors.initials: TD
authors.lastname: Wu
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Guerquin-Kern
authors.forename: Hyman M
authors.initials: HM
authors.lastname: Schipper
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology*
chemical_list: D007501:Iron; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1