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Activation of sirtuin 1 attenuates cerebral ventricular streptozotocin-induced tau hyperphosphorylation and cognitive injuries in rat hippocampi

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Abstract

Patients with diabetes in the aging population are at high risk of Alzheimer's disease (AD), and reduction of sirtuin 1 (SIRT1) activity occurs simultaneously with the accumulation of hyperphosphorylated tau in the AD-affected brain. It is not clear, however, whether SIRT1 is a suitable molecular target for the treatment of AD. Here, we employed a rat model of brain insulin resistance with intracerebroventricular injection of streptozotocin (ICV-STZ; 3 mg/kg, twice with an interval of 48 h). The ICV-STZ-treated rats were administrated with resveratrol (RSV; SIRT1-specific activator) or a vehicle via intraperitoneal injection for 8 weeks (30 mg/kg, once per day). In ICV-STZ-treated rats, the levels of phosphorylated tau and phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2) at the hippocampi were increased significantly, whereas SIRT1 activity was decreased without change of its expression level. The capacity of spatial memory was also significantly lower in ICV-STZ-treated rats compared with age-matched control. RSV, a specific activator of SIRT1, which reversed the ICV-STZ-induced decrease in SIRT1 activity, increases in ERK1/2 phosphorylation, tau phosphorylation, and impairment of cognitive capability in rats. In conclusion, SIRT1 protects hippocampus neurons from tau hyperphosphorylation and prevents cognitive impairment induced by ICV-STZ brain insulin resistance with decreased hippocampus ERK1/2 activity.

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Acknowledgments

This work was supported by the National Nature Scientific Fund of China (no. 81171196) and the National Key Technology Research and Development Program of the Ministry of Science and Technology of China (no. 2012BAI10B03). CC was supported by the Australian NHMRC.

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Authors and Affiliations

  1. Department of Pathophysiology, Key Laboratory of Neurological Diseases of Education Ministry of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Lai-Ling Du, Jia-Zhao Xie, Xiang-Shu Cheng, Xiao-Hong Li, Fan-Li Kong, Xia Jiang, Zhi-Wei Ma, Jian-Zhi Wang & Xin-Wen Zhou

  2. School of Biomedical Sciences, University of Queensland, Brisbane, QLD, 4072, Australia

    Chen Chen

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  1. Lai-Ling Du
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  2. Jia-Zhao Xie
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  10. Xin-Wen Zhou
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Correspondence to Xin-Wen Zhou.

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Lai-Ling Du and Jia-Zhao Xie contributed equally to this work

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Du, LL., Xie, JZ., Cheng, XS. et al. Activation of sirtuin 1 attenuates cerebral ventricular streptozotocin-induced tau hyperphosphorylation and cognitive injuries in rat hippocampi. AGE 36, 613–623 (2014). https://doi.org/10.1007/s11357-013-9592-1

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