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Atorvastatin ameliorates cognitive impairment, Aβ1-42 production and Tau hyperphosphorylation in APP/PS1 transgenic mice

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Abstract

Amyloid-beta (Aβ) interacts with the serine/threonine protein kinase AKT (also known as protein kinase B)/glycogen synthase kinase 3β (GSK3β) pathway and deactivates GSK3β signaling, which result in microtubule protein tau phosphorylation. Atorvastatin, a HMG-CoA reductase inhibitor, has been proven to improve learning and memory performance, reduce Aβ 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/GSK3β signaling and contributes to subsequent down-regulation of Aβ1-42 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/GSK3β 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 Aβ1-42 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 GSK3β activity by increasing phosphorylation of GSK3β (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/GSK3β signaling which may contribute to down-regulation of Aβ1-42 and tau hyperphosphorylation.

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Acknowledgments

This work was supported by National Natural Science Foundation of China (No. 81201050; No.81271209; No.81371224; No.81541087); Natural Science Foundation of Zhejiang province (No.LQ12H09001); Natural Science Foundation of Ningbo (No. 2012A610249); The Open Research Fund of State Key Laboratory of Bioelectronics, Southeast University (to Junfang Zhang) and Zhejiang “Climbing Program” (PD2013104). This project is also sponsored by K.C. Wong Magna funded at Ningbo University.

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    1. Ningbo Kangning Hospital, Ningbo, Zhejiang, 315210, People’s of Republic China

      Dongsheng Zhou, Yaosheng Shi, Lingjiang Liu & Zhongming Chen

    2. Ningbo Key Laboratory of Behavioral Neuroscience, Ningbo University School of Medicine, 818 Fenghua Road, Ningbo, Zhejiang, 315211, People’s of Republic China

      Dongsheng Zhou, Chenli Li, Yaosheng Shi, Lingjiang Liu, Xin Zhao, Aiming Liu, Junfang Zhang, Chuang Wang & Zhongming Chen

    3. School of Nursing, Taishan Medical University, Taian, Shandong, 271016, People’s of Republic China

      Huaxia Liu

    4. Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, 818 Fenghua Road, Ningbo, Zhejiang, 315211, People’s of Republic China

      Chenli Li, Fangyan Wang, Xin Zhao & Aiming Liu

    5. Department of Pathophysiology, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s of Republic China

      Junfang Zhang & Chuang Wang

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    1. Dongsheng Zhou
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    Correspondence to Junfang Zhang, Chuang Wang or Zhongming Chen.

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    Dongsheng Zhou, Huaxia Liu, Chenli Li and Fangyan Wang contributed equally to this work.

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    Zhou, D., Liu, H., Li, C. et al. Atorvastatin ameliorates cognitive impairment, Aβ1-42 production and Tau hyperphosphorylation in APP/PS1 transgenic mice. Metab Brain Dis 31, 693–703 (2016). https://doi.org/10.1007/s11011-016-9803-4

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