Deferoxamine inhibits iron induced hippocampal tau phosphorylation in the Alzheimer transgenic mouse brain |
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Authors: | Chuang Guo Pu Wang Man-Li Zhong Tao Wang Xue-Shi Huang Jia-Yi Li Zhan-You Wang |
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Institution: | 1. College of Life and Health Sciences, Northeastern University, Shenyang 110004, PR China;2. Department of Anatomy, Hebei United University at Qinhuangdao, Qinhuangdao 066001, PR China;3. Department of Pathophysiology, China Medical University, Shenyang 110001, PR China |
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Abstract: | 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 3β (GSK3β), 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 GSK3β pathways. More importantly, elucidation of DFO mechanism in suppressing tau phosphorylation may provide insights for developing therapeutic strategies to combat AD. |
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Keywords: | Aβ amyloid-β AD Alzheimer&rsquo s disease APP amyloid precursor protein CDK5 cyclin dependent kinase 5 DFO deferoxamine DMT1 divalent metal transporter 1 GAPDH glyceraldehyde 3-phosphate dehydrogenase GSK3β glycogen synthase kinase 3β HRP horseradish peroxidase NFTs intracellular neurofibrillary tangles PHFs paired helical filaments PS1 presenilin 1 TBS Tris-buffered saline |
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