title: Chronic hypoxia facilitates Alzheimer's disease through demethylation of γ-secretase by downregulating DNA methyltransferase 3b.
abstract: BACKGROUND
  Environmental factors and epigenetic mechanisms are believed to contribute to Alzheimer's disease (AD). We previously documented that prenatal hypoxia aggravated the cognitive impairment and neuropathology in offspring mice. Here, we investigate the chronic hypoxia-induced epigenetic modifications in AD.
  
  
  METHODS
  The 3-month-old APP(swe)/PS1(dE9) mice were exposed to hypoxic environment 6 hour/day for 30 days, followed by learning and memory tests and biochemical and neuropathology measurement at the age of 4, 6, and 9 months.
  
  
  RESULTS
  We found hypoxia exaggerated the neuropathology and cognitive impairment in AD mice. Chronic hypoxia induced demethylation on genomic DNA and decreased the expression of DNA methyltransferase 3b (DNMT3b) in vivo. We further found that DNMTs inhibition elevated the protein levels of amyloid precursor protein, β- and γ-secretases, whereas overexpression of DNMT3b suppressed the levels of them in vitro.
  
  
  CONCLUSIONS
  Our study suggests chronic hypoxia can aggravate AD progression through demethylation of genes encoding γ-secretase components by downregulation of DNMT3b.
authors.affiliation: Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Qiu
authors.affiliation: Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China.
authors.forename: Juan
authors.initials: J
authors.lastname: Yang
authors.affiliation: Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ni
authors.affiliation: Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China; Center for Translational Research on Neurological Diseases, 1st Affiliated Hospital, Dalian Medical University, Dalian, PR China. Electronic address: wdle@sibs.ac.cn.
authors.forename: Weidong
authors.initials: W
authors.lastname: Le
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000473:pathology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D000860:Hypoxia / Q000150:complications; D008568:Memory / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D000097584:DNA Methyltransferase 3B
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor; D004248:DNA (Cytosine-5-)-Methyltransferases; D000097584:DNA Methyltransferase 3B
keywords: Alzheimer's disease; Chronic hypoxia; DNA methylation; DNMT3a; DNMT3b; β-amyloid; γ-secretase