Valproic Acid Reduces Neuritic Plaque Formation and Improves Learning Deficits in APP Swe / PS 1 A246E Transgenic Mice via Preventing the Prenatal Hypoxia‐Induced Down‐Regulation of Neprilysin

摘要

Summary Aims Previously, we have documented that prenatal hypoxia can aggravate the cognitive impairment and A lzheimer's disease ( AD ) neuropathology in APP Swe/ PS 1A246E ( APP / PS 1) 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 / PS 1 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 A β neuropathology, learning, and memory. Chromatin immunoprecipitation ( C h IP ) assays and real‐time PCR ( RT ‐ PCR ) were used to determine the effect of VPA on the histone3 acetylation ( H 3‐ A ce). Results We found that VPA can inhibit neuritic plaque formation and improve the learning and memory in the prenatal hypoxic APP / PS 1 transgenic mice. In addition, VPA treatment can decrease the soluble and insoluble A β42 levels and increase the NEP expression via up‐regulation of H 3‐ A ce in the APP / PS 1 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 ( HDAC 1), preventing the decrease in H 3‐ A ce in the NEP promoter regions and reducing the down‐regulation of NEP .