title: Dose-specific effect of simvastatin on hypoxia-induced HIF-1α and BACE expression in Alzheimer's disease cybrid cells.
abstract: BACKGROUND
  Alzheimer's disease (AD) is associated with vascular risk factors; brain ischemia facilitates the pathogenesis of AD. Recent studies have suggested that the reduction of AD risk with statin was achieved by decreased amyloidogenic amyloid precursor protein.
  
  
  METHODS
  We used mitochondrial transgenic neuronal cell (cybrid) models to investigate changes in the levels of intracellular hypoxia inducible factor 1α (HIF-1α) and β-site amyloid precursor protein cleaving enzyme (BACE) in the presence of simvastatin. Sporadic AD (SAD) and age-matched control (CTL) cybrids were exposed to 2% O2 and incubated with 1 μM or 10 μM simvastatin.
  
  
  RESULTS
  There was no significant difference between cell survival by 1 or 10 μM simvastatin in both SAD and CTL cybrids. In the presence of 1 μM simvastatin, intracellular levels of HIF-1α and BACE decreased by 40-70% in SAD, but not CTL cybrids. However, 10 μM simvastatin increased HIF-1α and BACE expression in both cybrid models.
  
  
  CONCLUSIONS
  Our results suggest demonstrate differential dose-dependent effects of simvastatin on HIF-1α and BACE in cultured Alzheimer's disease cybrid cells.
authors.affiliation: Department of Neurology, College of Medicine, Chungbuk National University, Chungbuk National University Hospital, Cheongju, Korea. nr.jungjh@gmail.com.
authors.forename: Jin-Heon
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Department of Neurology, College of Medicine, Konyang University, Konyang University Hospital, Daejeon, Korea. yum5665@hanmail.net.
authors.forename: Kyu Sun
authors.initials: KS
authors.lastname: Yum
authors.affiliation: Department of Neurology, College of Medicine, Seoul National University, Seoul National University Bundang Hospital, Seongnam, Korea. kjychang@gmail.com.
authors.forename: Jun Young
authors.initials: JY
authors.lastname: Chang
authors.affiliation: Department of Neurology, College of Medicine, Seoul National University, Seoul National University Hospital, Seoul, Korea. kimmanho@snu.ac.kr.
authors.forename: Manho
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Neurology, Seoul Medical Center, Seoul, Korea. neuroahn@gmail.com.
authors.forename: Jin-young
authors.initials: JY
authors.lastname: Ahn
authors.affiliation: Department of Neurology, College of Medicine, Seoul National University, Seoul National University Bundang Hospital, Seongnam, Korea. neuroksy@snu.ac.kr.
authors.forename: SangYun
authors.initials: S
authors.lastname: Kim
authors.affiliation: Departments of Neurology and Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, USA. Paul.Lapchak@cshs.org.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Lapchak
authors.affiliation: Department of Neurology, College of Medicine, Seoul National University, Seoul National University Bundang Hospital, Seongnam, Korea. mkhan@snu.ac.kr.
authors.forename: Moon-Ku
authors.initials: MK
authors.lastname: Han
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007118:Immunoassay; D008928:Mitochondria / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D012307:Risk Factors; D019821:Simvastatin / Q000627:therapeutic use*
chemical_list: D004272:DNA, Mitochondrial; C497442:HIF1A protein, human; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019821:Simvastatin; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human