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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >13-Desmethyl spirolide-C is neuroprotective and reduces intracellular Aβ and hyperphosphorylated tau in vitro
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13-Desmethyl spirolide-C is neuroprotective and reduces intracellular Aβ and hyperphosphorylated tau in vitro

机译：13-去甲基螺螺内酯-C具有神经保护作用，并能在体外降低细胞内Aβ和磷酸化tau

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摘要

Spirolides are marine compounds of the cyclic imine group. Although the mechanism of action is not fully elucidated yet, cholinergic (muscarinic and nicotinic) receptors have been proposed as the main targets of these toxins. In this study we examined the effect of 13-desmethyl spirolide-C (SPX) on amyloid-beta (Aβ) accumulation and tau hyperphosphorylation in a neuronal model from triple transgenic mice (3xTg) for Alzheimer disease (AD). In vitro treatment of 3xTg cortical neurons with SPX reduced intracellular Aβ accumulation and the levels of phosphorylated tau. SPX treatment did not affect the steady-state levels of neither the M1 and M2 muscarinic nor the α7 nicotinic acetylcholine receptors (AChRs), while it decreased the amplitude of acetylcholine-evoked responses and increased ACh (acetylcholine) levels in 3xTg neurons. Additionally, SPX treatment decreased the levels of two protein kinases involved in tau phosphorylation, glycogen synthase kinase 3β (GSK-3β) and extracellular-regulated kinase (ERK). Also SPX abolished the glutamate-induced neurotoxicity in both control and 3xTg neurons. The results presented here constitute the first report indicating that exposure of 3xTg neurons to nontoxic concentrations of SPX produces a simultaneous reduction in the main pathological characteristics of AD. In spite of the few reports analyzing the mode of action of the toxin we suggest that SPX could ameliorate AD pathology increasing the intracellular ACh levels and simultaneously diminishing the levels of kinases involved in tau phosphorylation.
机译：螺旋化物是环状亚胺基的海洋化合物。尽管尚未完全阐明其作用机理，但已提出胆碱能（毒蕈碱和烟碱酸）受体是这些毒素的主要靶标。在这项研究中，我们检查了13-desmethyl spirolide-C（SPX）对三重转基因小鼠（3xTg）患阿尔茨海默氏病（AD）的神经元模型中淀粉样β（Aβ）积累和tau过度磷酸化的影响。用SPX体外处理3xTg皮质神经元可减少细胞内Aβ积累和磷酸化tau的水平。 SPX处理不影响M1和M2毒蕈碱或α7烟碱乙酰胆碱受体（AChRs）的稳态水平，而它却降低了3xTg神经元中乙酰胆碱引起的反应的幅度并增加了ACh（乙酰胆碱）的水平。另外，SPX处理降低了涉及tau磷酸化的两种蛋白激酶，糖原合酶激酶3β（GSK-3β）和细胞外调节激酶（ERK）的水平。 SPX还消除了谷氨酸诱导的对照和3xTg神经元神经毒性。此处提供的结果构成了第一个报告，表明3xTg神经元暴露于无毒浓度的SPX会同时降低AD的主要病理特征。尽管很少有报道分析毒素的作用方式，但我们认为SPX可以改善AD病理，增加细胞内ACh的水平，同时降低tau磷酸化所涉及的激酶的水平。

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