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CNS Neurosci Ther. 2014 Mar;20(3):209-17. doi: 10.1111/cns.12186. Epub 2013 Dec 2.

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.

Author information

1
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.

Abstract

AIMS:

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.

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.

KEYWORDS:

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

PMID:
24289518
DOI:
10.1111/cns.12186
[Indexed for MEDLINE]

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