Department of Neurology, The 4th Affiliated Hospital of China Medical University, Shenyang, 110032, China.
J Mol Neurosci. 2013 Sep;51(1):138-47. doi: 10.1007/s12031-013-9966-y. Epub 2013 Jan 24.
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.
慢性缺氧已被报道有助于阿尔茨海默病（AD）的发展。然而，缺氧在 AD 发病机制中的作用机制尚不清楚。本研究旨在探讨慢性缺氧处理对 APP/PS1 双转基因小鼠β-淀粉样蛋白、tau 病理学和行为后果的影响。用缺氧处理双转基因小鼠（APP/PS1 小鼠），并在 Morris 水迷宫中评估小鼠的空间学习和记忆能力。通过免疫组织化学检测 APP/PS1 双转基因小鼠中的β-淀粉样蛋白水平和斑块水平。通过 Western blot 分析检测蛋白 tau、p35/p25、细胞周期蛋白依赖性激酶 5（CDK5）和钙蛋白酶。慢性缺氧处理可降低 AD 小鼠的记忆和认知功能。此外，慢性缺氧处理导致老年斑增加，同时伴有 tau 磷酸化增加。缺氧诱导的 tau 磷酸化增加与 p35 和 p25 的产生显著增加以及钙蛋白酶的上调有关，表明缺氧通过上调钙蛋白酶诱导异常的 CDK5/p25 激活。我们的结果表明，慢性缺氧暴露不仅通过钙蛋白酶介导的 tau 过度磷酸化加速了 AD 小鼠模型中的淀粉样蛋白病理学，而且加速了 tau 病理学。这些病理变化可能导致 AD 小鼠缺氧诱导的行为变化。
