Valproic acid reduces neuritic plaque formation and improves learning deficits in APPSwe/PS1A246E transgenic mice via preventing the prenatal hypoxia-induced down-regulation of neprilysin

Zheng Wang, Xiao Jie Zhang, Ting Li, Jia Li, Yu Tang, Weidong Le

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Aims: Previously, we have documented that prenatal hypoxia can aggravate the cognitive impairment and Alzheimer's disease (AD) neuropathology in APPSwe/PS1A246E (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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)209-217
Number of pages9
JournalCNS Neuroscience and Therapeutics
Volume20
Issue number3
DOIs
StatePublished - Mar 2014

Keywords

  • Alzheimer's Disease
  • Neprilysin
  • Prenatal Hypoxia
  • Valproic Acid

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Physiology (medical)
  • Psychiatry and Mental health
  • Pharmacology

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