Ginsenoside Rd attenuates beta-amyloid-induced tau phosphorylation by altering the functional balance of glycogen synthase kinase 3beta and protein phosphatase 2A
Ginsenoside Rd attenuates beta-amyloid-induced tau phosphorylation by altering the functional balance of glycogen synthase kinase 3beta and protein phosphatase 2A
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人参皂苷 Rd 通过改变糖原合成酶激酶 3beta 和蛋白磷酸酶 2A 的功能平衡来减弱 β-淀粉样蛋白诱导的 tau 磷酸化
DOI：
10.1016/j.nbd.2013.01.002
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发表时间：
2013-06-01
影响因子：
6.1
通讯作者：
Zhao, Gang
中科院分区：
文献类型：
--
作者：
Li, Ling;Liu, Zhirong;Zhao, Gang
神经元缠结是过度磷酸化的tau的聚集体，其是阿尔茨海默病（AD）的病理学标志之一。Tau磷酸化受激酶和磷酸酶活性的平衡调节。我们前期的研究表明三七主要活性成分之一的三七皂苷Rd在体内和体外均能抑制冈田酸诱导的tau蛋白磷酸化，但其机制尚不清楚。在这项研究中，我们发现，在β-淀粉样蛋白（A β）处理的培养的皮层神经元，并在体内大鼠和转基因小鼠模型中，在多个网站上抑制tau蛋白磷酸化。人参皂苷Rd不仅降低A β诱导的糖原合成酶激酶3 β（GSK-3 β）（参与tau磷酸化的最重要的激酶）的表达增加，而且通过分别增强和减弱其在Ser 9和Tyr 216处的磷酸化来抑制其活性。此外，PDR-Rd增强了蛋白磷酸酶2A（PP-2A）的活性，这是一种参与tau去磷酸化的关键磷酸酶。最后，体外生物化学测定显示，CYP 1 Rd直接影响GSK-3 β和PP-2A活性。因此，我们的研究结果提供了第一个证据，即BERN-Rd通过改变GSK-3 β和PP-2A的功能平衡来减弱A β诱导的病理性tau磷酸化。(c)2013 Elsevier Inc. All rights reserved.
Neurofibrillary tangles are aggregates of hyperphosphorylated tau that are one of the pathological hallmarks of Alzheimer's disease (AD). Tau phosphorylation is regulated by a balance of kinase and phosphatase activities. Our previous study has demonstrated that ginsenoside Rd, one of the principal active ingredients of Pana notoginseng, inhibits okadaic acid-induced tau phosphorylation in vivo and in vitro, but the underlying mechanism(s) is unknown. In this study, we showed that ginsenoside Rd pretreatment inhibited tau phosphorylation at multiple sites in beta-amyloid (A beta)-treated cultured cortical neurons, and in vivo in both a rat and transgenic mouse model. Ginsenoside Rd not only reduced A beta-induced increased expression of glycogen synthase kinase 3beta (GSK-3 beta), the most important kinase involved in tau phosphorylation, but also inhibited its activity by enhancing and attenuating its phosphorylation at Ser9 and Tyr216, respectively. Moreover, ginsenoside Rd enhanced the activity of protein phosphatase 2A (PP-2A), a key phosphatase involved in tau dephosphorylation. Finally, an in vitro biochemical assay revealed that ginsenoside Rd directly affected GSK-3 beta and PP-2A activities. Thus, our findings provide the first evidence that ginsenoside Rd attenuates A beta-induced pathological tau phosphorylation by altering the functional balance of GSK-3 beta and PP-2A. (c) 2013 Elsevier Inc. All rights reserved.