Valproic acid attenuates neuronal apoptosis in APP/PS1 transgenic Alzheimer′s disease mice model

Abstract

One of the hallmarks of Alzheimer's disease (AD) is the accumulation of senile plaques(SP) composed of extracellular aggregates of amyloid ¦Â peptides (A¦Â). It is proved that A¦Â 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 AD model mice. The present study intended to explore the protective effect of VPA on neuronal apoptosis in transgenic AD model mice and the possible mechanisms involved. Immunohistochemical staining showed that VPA reduced the number of swollen neurons and promoted neurite outgrowth in AD mice. MTT assay and Tunel staining showed that VPA increased cell viability and reduced the number of apoptotic cells. Western blot revealed that VPA downregulated the expression of Caspase‐ 3, Caspase‐9 and Caspase‐12, reduced cytochrome C level. The expression of Bcl‐2 was increased by VPA treatment. Flow cytometry revealed that VPA decreased intracellular level of Ca2+ and elevated mitochondrial membrane potential. Our results indicate that VPA protected AD mice model via inhibition of both mitochondrial and endoplasmic reticulum pathway of apoptosis.This work was supported by National Natural Science Foundation of China (30970986).