title: Neural HO-1/sterol interactions in vivo: implications for Alzheimer's disease.
abstract: BACKGROUND
  Up-regulation of heme oxygenase-1 (HO-1) and altered cholesterol (CH) metabolism are characteristic of Alzheimer-diseased (AD) neural tissues. We previously provided evidence of significant HO-1/sterol interactions in vitro (cultured rat astroglia) and in post-mortem human AD brain (Religious Orders Study).
  
  
  METHODS
  The current experiments were designed to further delineate these interactions in vivo by comparing the behavior of HO-1/sterol interactions in two mouse models; (1) a novel HO-1 transgenic mouse (GFAP.HMOX1) engineered to selectively express human HO-1 in the astrocytic compartment and (2) the previously described triple transgenic AD mouse (3xTg-AD). In samples of frontal cortex, total CH, CH precursors and relevant oxysterols were quantified by gas chromatography-mass spectrometry (GC-MS) and HO-1 protein expression was assessed by ELISA. The relationships of HO-1 expression to total CH, CH precursors and total oxysterols were determined for both mouse models using linear regression analysis.
  
  
  RESULTS
  HO-1 expression is increased in GFAP.HMOX1 mice relative to wild type and in 11-12-month-old 3xTg-AD mice (with AD-like phenotype) relative to control mice and 5-6-month-old 3xTg-AD mice (no AD-like phenotype). Total oxysterols significantly decreased as HO-1 expression increased in GFAP.HMOX1 mice expressing high levels of HO-1, whereas total oxysterols increased as HO-1 expression increased in aged 3xTg-AD mice. Total CH and total CH precursors increased as HO-1 protein expression increased in 11-12-month-old 3xTg-AD mice relative to 5-6-month old 3xTg-AD mice.
  
  
  CONCLUSIONS
  Our findings indicate a differential impact of HO-1 on patterns of brain sterol and redox homeostasis that is contingent on the presence or absence of AD-like neuropathology. These data provide fresh insight concerning the regulation of sterol homeostasis within the aging and degenerating CNS which may inform the development of novel therapeutic and preventive strategies for the management of AD and related conditions.
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote Sainte Catherine Road, Montreal, Quebec H3T 1E2, Canada; Department of Neurology and Neurosurgery, McGill University, Jewish General Hospital, 3755 Cote Sainte Catherine Road, Montreal, Quebec H3T 1E2, Canada.
authors.forename: J R
authors.initials: JR
authors.lastname: Hascalovici
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote Sainte Catherine Road, Montreal, Quebec H3T 1E2, Canada.
authors.forename: W
authors.initials: W
authors.lastname: Song
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote Sainte Catherine Road, Montreal, Quebec H3T 1E2, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Liberman
authors.affiliation: Laboratory of Natural Medicinal Compounds, Migal-Galilee Technological Center and Tel Hai College, Kiryat-Shmona 11016, Israel.
authors.forename: J
authors.initials: J
authors.lastname: Vaya
authors.affiliation: Laboratory of Natural Medicinal Compounds, Migal-Galilee Technological Center and Tel Hai College, Kiryat-Shmona 11016, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Khatib
authors.affiliation: Centre for Clinical Epidemiology and Community Studies, Jewish General Hospital, 3755 Cote Sainte Catherine Road, Montreal, Quebec H3T 1E2, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Holcroft
authors.affiliation: Department of Neurobiology and Behavior and Institute for Brain Aging and Dementia, University of California, Irvine, Irvine, CA 92697-4545, USA.
authors.forename: F
authors.initials: F
authors.lastname: Laferla
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote Sainte Catherine Road, Montreal, Quebec H3T 1E2, Canada; Department of Neurology and Neurosurgery, McGill University, Jewish General Hospital, 3755 Cote Sainte Catherine Road, Montreal, Quebec H3T 1E2, Canada. Electronic address: hyman.schipper@mcgill.ca.
authors.forename: H M
authors.initials: HM
authors.lastname: Schipper
mesh_terms: D000375:Aging / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein; D057809:HEK293 Cells; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D013261:Sterols / Q000378:metabolism*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D005904:Glial Fibrillary Acidic Protein; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D013261:Sterols; C528900:glial fibrillary astrocytic protein, mouse; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
keywords: Alzheimer’s disease; astrocyte; cholesterol; heme oxygenase-1; lipid; oxysterol