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Dysregulation of Na+/K+ ATPase by amyloid in APP+PS1 transgenic mice

机译：淀粉样蛋白对APP + PS1转基因小鼠中Na + / K + ATPase的异常调节

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Background The pathology of Alzheimer's disease (AD) is comprised of extracellular amyloid plaques, intracellular tau tangles, dystrophic neurites and neurodegeneration. The mechanisms by which these various pathological features arise are under intense investigation. Here, expanding upon pilot gene expression studies, we have further analyzed the relationship between Na+/K+ ATPase and amyloid using APP+PS1 transgenic mice, a model that develops amyloid plaques and memory deficits in the absence of tangle formation and neuronal or synaptic loss. Results We report that in addition to decreased mRNA expression, there was decreased overall Na+/K+ ATPase enzyme activity in the amyloid-containing hippocampi of the APP+PS1 mice (although not in the amyloid-free cerebellum). In addition, dual immunolabeling revealed an absence of Na+/K+ ATPase staining in a zone surrounding congophilic plaques that was occupied by dystrophic neurites. We also demonstrate that cerebral Na+/K+ ATPase activity can be directly inhibited by high concentrations of soluble Aβ. Conclusions The data suggest that the reductions in Na+/K+ ATPase activity in Alzheimer tissue may not be purely secondary to neuronal loss, but may results from direct effects of amyloid on this enzyme. This disruption of ion homeostasis and osmotic balance may interfere with normal electrotonic properties of dendrites, blocking intraneuronal signal processing, and contribute to neuritic dystrophia. These results suggest that therapies aimed at enhancing Na+/K+ ATPase activity in AD may improve symptoms and/or delay disease progression.
机译：背景阿尔茨海默氏病（AD）的病理学包括细胞外淀粉样斑块，细胞内tau缠结，营养不良的神经突和神经退行性变。这些各种病理学特征出现的机制正在深入研究中。在这里，通过先导基因表达研究的扩展，我们使用APP + PS1转基因小鼠进一步分析了Na + / K + ATPase与淀粉样蛋白之间的关系，该模型在没有缠结形成和神经元或突触丢失的情况下会产生淀粉样斑块和记忆缺陷。结果我们报告说，除了mRNA表达下降外，APP + PS1小鼠的含淀粉样海马体中的总Na + / K + ATPase活性也降低了（尽管不含淀粉样蛋白的小脑中没有）。另外，双重免疫标记显示在营养不良的神经突所占据的亲血斑周围的区域中不存在Na + / K + ATPase染色。我们还证明，高浓度的可溶性Aβ可以直接抑制脑Na + / K + ATPase活性。结论数据表明，阿尔茨海默氏病组织中Na + / K + ATPase活性的降低可能不是单纯的继发于神经元丧失，而可能是淀粉样蛋白对该酶的直接作用所致。离子稳态和渗透平衡的这种破坏可能会干扰树突的正常电渗性质，阻碍神经内信号处理，并导致神经营养不良。这些结果表明，旨在增强AD中Na + / K + ATPase活性的疗法可能会改善症状和/或延缓疾病进展。

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