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.