Valproic Acid Attenuates Neuronal Loss in the Brain of APP/PS1 Double Transgenic Alzheimer’s Disease Mice Model

Zhimin      Long; Min      Zheng; Lei      Zhao; Peng      Xie; Cong      Song; Yalan      Chu; Weihong      Song; Guiqiong      He

doi:10.2174/1567205011310030005

Abstract

Alzheimer's disease (AD) is characterized by senile plaques (SP) of extracellular amyloid β peptides(Aβ), neurofibrillary tangles (NFT) of intracellular hyper-phosphorylated tau and widespread loss of neurons. Apoptosis is the main reason of neuronal loss. It is proved that Aβ triggers apoptotic cell death via the activation of caspase-dependent and - independent cell death effectors, respectively. Valproic acid (VPA) is a widely used mood stabilizer and antiepileptic drug. Our previous study showed that VPA treatment significantly reduced SP formation and improved memory deficits in transgenic AD model mice. The present study intended to explore the protective effect of VPA on neuronal loss in transgenic AD model mice and the possible mechanisms involved. Histological and ultra-structural analysis showed that VPA partially decreased the swollen mitochondria and neurophil and promoted neurite outgrowth in AD mice model. Meanwhile, VPA greatly rescued the neuronal loss in the brain of AD mice. TUNEL staining showed that VPA significantly reduced the number of apoptotic cells. Western blot analysis revealed that VPA notably down-regulated the expression of Caspase-3, Caspase-9 and Caspase-12, reduced the level of cytochrome C and Bax. The expression of the antiapoptotic protein Bcl-2 was increased after VPA treatment. Flow cytometry revealed that VPA significantly decreased intracellular level of Ca²⁺ and elevated mitochondrial membrane potential. Altogether, these results indicate that VPA protected AD mice via suppression of upstream factors of apoptosis, namely inhibition of both mitochondrial and endoplasmic reticulum pathway of apoptosis.

Keywords: Valproic acid, GSK-3β, apoptosis, Alzheimer’s disease

« Previous Next »