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Hypoxia Increases Aβ-Induced Tau Phosphorylation by Calpain and Promotes Behavioral Consequences in AD Transgenic Mice

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Abstract

Chronic hypoxia has been reported to contribute to the development of Alzheimer’s disease (AD). However, the mechanism of hypoxia in the pathogenesis of AD remains unclear. The purpose of this study was to investigate the effects of chronic hypoxia treatment on β-amyloid, tau pathologies, and the behavioral consequences in the double transgenic (APP/PS1) mice. Double transgenic mice (APP/PS1 mice) were treated with hypoxia, and spatial learning and memory abilities of mice were assessed in the Morris water maze. β-amyloid level and plaque level in APP/PS1 double transgenic mice were detected by immunohistochemistry. Protein tau, p35/p25, cyclin-dependent kinase 5 (CDK5), and calpain were detected by western blotting analysis. Chronic hypoxia treatment decreased memory and cognitive function in AD mice. In addition, chronic hypoxia treatment resulted in increased senile plaques, accompanying with increased tau phosphorylation. The hypoxia-induced increase in the tau phosphorylation was associated with a significant increase in the production of p35 and p25 and upregulation of calpain, suggesting that hypoxia induced aberrant CDK5/p25 activation via upregulation of calpain. Our results showed that chronic hypoxia exposure accelerates not only amyloid pathology but also tau pathology via calpain-mediated tau hyperphosphorylation in an AD mouse model. These pathological changes possibly contribute to the hypoxia-induced behavioral change in AD mice.

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  1. Department of Neurology, The 4th Affiliated Hospital of China Medical University, Shenyang, 110032, China

    Lianbo Gao, Shen Tian, Honghua Gao & Yanyuan Xu

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  1. Lianbo Gao
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  2. Shen Tian
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  3. Honghua Gao
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Correspondence to Lianbo Gao.

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Gao, L., Tian, S., Gao, H. et al. Hypoxia Increases Aβ-Induced Tau Phosphorylation by Calpain and Promotes Behavioral Consequences in AD Transgenic Mice. J Mol Neurosci 51, 138–147 (2013). https://doi.org/10.1007/s12031-013-9966-y

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