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铁过载加速阿尔茨海默病转基因小鼠模型中的神经元淀粉样β蛋白生成和认知障碍。

Iron overload accelerates neuronal amyloid-β production and cognitive impairment in transgenic mice model of Alzheimer's disease.

作者信息

Becerril-Ortega Javier, Bordji Karim, Fréret Thomas, Rush Travis, Buisson Alain

机构信息

INSERM, U836, BP 170, Grenoble Cedex 9, F-38042, France; Université Joseph Fourier, Grenoble Institut des Neurosciences, BP 170, Grenoble Cedex 9, F-38042, France.

Université de Caen-Basse Normandie, GIP Cyceron, CNRS UMR 6301 ISTCT, CERVOxy Group, Caen, France.

出版信息

Neurobiol Aging. 2014 Oct;35(10):2288-301. doi: 10.1016/j.neurobiolaging.2014.04.019. Epub 2014 May 1.

Abstract

Iron dyshomeostasis is proving increasingly likely to be involved in the pathology of Alzheimer's disease (AD); yet, its mechanism is not well understood. Here, we investigated the AD-related mechanism(s) of iron-sulfate exposure in vitro and in vivo, using cultured primary cortical neurons and APP/PS1 AD-model mice, respectively. In both systems, we observed iron-induced disruptions of amyloid precursor protein (APP) processing, neuronal signaling, and cognitive behavior. Iron overload increased production of amyloidogenic KPI-APP and amyloid beta. Further, this APP misprocessing was blocked by MK-801 in vitro, suggesting the effect was N-methyl-D-aspartate receptor (NMDAR) dependent. Calcium imaging confirmed that 24 hours iron exposure led to disrupted synaptic signaling by augmenting GluN2B-containing NMDAR expression-GluN2B messenger RNA and protein levels were increased and promoting excessing extrasynaptic NMDAR signaling. The disrupted GluN2B expression was concurrent with diminished expression of the splicing factors, sc35 and hnRNPA1. In APP/PS1 mice, chronic iron treatment led to hastened progression of cognitive impairment with the novel object recognition discrimination index, revealing a deficit at the age of 4 months, concomitant with augmented GluN2B expression. Together, these data suggest iron-induced APP misprocessing and hastened cognitive decline occur through inordinate extrasynaptic NMDAR activation.

摘要

铁稳态失衡越来越有可能参与阿尔茨海默病(AD)的病理过程;然而,其机制尚未完全清楚。在这里,我们分别使用原代培养的皮质神经元和APP/PS1 AD模型小鼠,在体外和体内研究了硫酸铁暴露与AD相关的机制。在这两个系统中,我们都观察到铁诱导的淀粉样前体蛋白(APP)加工、神经元信号传导和认知行为的破坏。铁过载增加了淀粉样生成性KPI-APP和β淀粉样蛋白的产生。此外,这种APP加工错误在体外被MK-801阻断,表明该效应依赖于N-甲基-D-天冬氨酸受体(NMDAR)。钙成像证实,24小时的铁暴露通过增加含GluN2B的NMDAR表达(GluN2B信使核糖核酸和蛋白质水平增加)和促进突触外NMDAR信号传导过度,导致突触信号传导中断。GluN2B表达的破坏与剪接因子sc35和hnRNPA1表达的减少同时发生。在APP/PS1小鼠中,慢性铁处理导致认知障碍进展加速,新物体识别辨别指数显示在4个月大时出现缺陷,同时GluN2B表达增加。总之,这些数据表明,铁诱导的APP加工错误和认知衰退加速是通过过度的突触外NMDAR激活发生的。

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