Send to

Choose Destination
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

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.



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.


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).


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.


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.


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

[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center