Deferoxamine inhibits iron induced hippocampal tau phosphorylation in the Alzheimer transgenic mouse brain
Deferoxamine inhibits iron induced hippocampal tau phosphorylation in the Alzheimer transgenic mouse brain
复制标题
去铁胺抑制阿尔茨海默病转基因小鼠大脑中铁诱导的海马 tau 蛋白磷酸化
DOI：
10.1016/j.neuint.2012.12.005
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发表时间：
2013-01-01
影响因子：
4.2
通讯作者：
Wang, Zhan-You
中科院分区：
文献类型：
--
作者：
Guo, Chuang;Wang, Pu;Wang, Zhan-You
先前的研究表明，铁与过度磷酸化的tau相互作用，这有助于阿尔茨海默病（AD）中神经元缠结（NFT）的形成，而铁螯合剂去铁胺（DFO）减缓了与这种疾病相关的认知衰退的临床进展。然而，在铁存在或不存在的情况下，DFO对tau磷酸化的影响尚未确定。以淀粉样前体蛋白（APP）和早老素1（PS1）双转基因小鼠脑为模型系统，研究DFO对铁诱导的tau蛋白异常磷酸化的影响及其可能机制。在APP/PS1转基因小鼠中，高剂量铁处理显著增加了Thr 205、Thr 231和Ser 396位点的tau磷酸化水平，而DFO鼻内给药消除了高度诱导的tau磷酸化。此外，DFO鼻内给药还降低了Fe诱导的细胞周期蛋白依赖性激酶5（CDK 5）和糖原合成酶激酶3 β（GSK 3 β）的活性，这反过来又抑制了tau蛋白磷酸化。累积起来，我们的数据显示鼻内DFO治疗通过CDK 5和GSK 3 β途径对铁诱导的tau磷酸化发挥其抑制作用。更重要的是，阐明DFO抑制tau磷酸化的机制可能为开发对抗AD的治疗策略提供见解。(C)2012爱思唯尔有限公司保留所有权利。
Prior work has shown that iron interacts with hyperphosphorylated tau, which contributes to the formation of neurofibrillary tangles (NFTs) in Alzheimer's disease (AD), whereas iron chelator desferrioxamine (DFO) slows down the clinical progression of the cognitive decline associated with this disease. However, the effects of DFO on tau phosphorylation in the presence or absence of iron have yet to be determined. Using amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mouse brain as a model system, we investigated the effects and potential mechanisms of intranasal administration of DFO on iron induced abnormal tau phosphorylation. High-dose iron treatment markedly increased the levels of tau phosphorylation at the sites of Thr205, Thr231 and Ser396, whereas highly induced tau phosphorylation was abolished by intranasal administration of DFO in APP/PS1 transgenic mice. Moreover, DFO intranasal administration also decreases Fe-induced the activities of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3 beta (GSK3 beta), which in turn suppressing tau phosphorylation. Cumulatively, our data show that intranasal DFO treatment exerts its suppressive effects on iron induced tau phosphorylation via CDK5 and GSK3 beta pathways. More importantly, elucidation of DFO mechanism in suppressing tau phosphorylation may provide insights for developing therapeutic strategies to combat AD. (C) 2012 Elsevier Ltd. All rights reserved.