Atorvastatin ameliorates cognitive impairment, A beta 1-42 production and Tau hyperphosphorylation in APP/PS1 transgenic mice

• Published in: Metabolic brain disease 2016-06, Vol.31 (3), p.693-703
• Main Authors: Zhou, Dongsheng, Liu, Huaxia, Li, Chenli, Wang, Fangyan, Shi, Yaosheng, Liu, Lingjiang, Zhao, Xin, Liu, Aiming, Zhang, Junfang, Wang, Chuang, Chen, Zhongming
• Format: Article
• Language: English
• ISSN: 0885-7490; 1573-7365
• DOI: 10.1007/s11011-016-9803-4

Amyloid-beta (A beta ) interacts with the serine/threonine protein kinase AKT (also known as protein kinase B)/glycogen synthase kinase 3 beta (GSK3 beta ) pathway and deactivates GSK3 beta signaling, which result in microtubule protein tau phosphorylation. Atorvastatin, a HMG-CoA reductase inhibitor, has been proven to improve learning and memory performance, reduce A beta and phosphorylated tau levels in mouse model of Alzheimer's disease (AD). However, it still remains unclear whether atorvastatin is responsible for regulation of AKT/GSK3 beta signaling and contributes to subsequent down-regulation of A beta 1-42 and phosphorylated tau in APP/PS1 transgenic (Tg APP/PS1) mice. Herein, we aimed to investigate the possible impacts of atorvastatin (10 mg/kg, p.o.) on the memory deficit by behavioral tests and changes of AKT/GSK3 beta signaling in hippocampus and prefrontal cortex by western blot test in Tg APP/PS1 mice. The results showed that treatment with atorvastatin significantly reversed the memory deficit in the Tg APP/PS1 mice in a novel object recognition and the Morris water maze tests. Moreover, atorvastatin significantly attenuated A beta 1-42 accumulation and phosphorylation of tau (Ser396) in the hippocampus and prefrontal cortex of Tg APP/PS1 mice. In addition, atorvastatin treatment also increased phosphorylation of AKT, inhibited GSK3 beta activity by increasing phosphorylation of GSK3 beta (Ser9) and decreasing the beta-site APP cleaving enzyme 1 (BACE1) expression. These results indicated that the memory ameliorating effect of atorvastatin may be, in part, by regulation the AKT/GSK3 beta signaling which may contribute to down-regulation of A beta 1-42 and tau hyperphosphorylation.