title: Valproic acid reduces neuritic plaque formation and improves learning deficits in APP(Swe) /PS1(A246E) transgenic mice via preventing the prenatal hypoxia-induced down-regulation of neprilysin.
abstract: OBJECTIVE
  Previously, we have documented that prenatal hypoxia can aggravate the cognitive impairment and Alzheimer's disease (AD) neuropathology in APP(Swe) /PS1(A246E) (APP/PS1) transgenic mice, and valproic acid (VPA) can prevent hypoxia-induced down-regulation of β-amyloid (Aβ) degradation enzyme neprilysin (NEP) in primary neurons. In this study, we have investigated the molecular mechanisms of VPA's anti-AD effects and found that VPA can reduce the prenatal hypoxia-induced neuritic plaque formation and improve the learning deficits in the AD mouse model.
  
  
  METHODS
  The pregnant APP/PS1 transgenic mice were exposed in a hypobaric chamber. Neuritic plaque staining, Morris water maze, and enzyme-linked immunosorbent assay (ELISA) were used to detect the effects of VPA on Aβ neuropathology, learning, and memory. Chromatin immunoprecipitation (ChIP) assays and real-time PCR (RT-PCR) were used to determine the effect of VPA on the histone3 acetylation (H3-Ace).
  
  
  RESULTS
  We found that VPA can inhibit neuritic plaque formation and improve the learning and memory in the prenatal hypoxic APP/PS1 transgenic mice. In addition, VPA treatment can decrease the soluble and insoluble Aβ42 levels and increase the NEP expression via up-regulation of H3-Ace in the APP/PS1 transgenic mice.
  
  
  CONCLUSIONS
  Valproic acid is able to attenuate the prenatal hypoxia-induced Aβ neuropathology and learning and memory deficits via inhibiting the activation of histone deacetylase 1 (HDAC1), preventing the decrease in H3-Ace in the NEP promoter regions and reducing the down-regulation of NEP.
authors.affiliation: Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; State Key Laboratory of Medical Neurobiology, Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Xiao-Jie
authors.initials: XJ
authors.lastname: Zhang
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Tang
authors.forename: Weidong
authors.initials: W
authors.lastname: Le
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D006801:Humans; D000860:Hypoxia; D007859:Learning Disabilities / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D015260:Neprilysin / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects* / Q000473:pathology; D058225:Plaque, Amyloid / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology*; D053764:Presenilin-1 / Q000235:genetics; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1; D014635:Valproic Acid; D015260:Neprilysin
keywords: Alzheimer's Disease; Neprilysin; Prenatal Hypoxia; Valproic Acid