C-Glycosylflavones Alleviate Tau Phosphorylation and Amyloid Neurotoxicity through GSK3β Inhibition.
C-Glycosylflavones Alleviate Tau Phosphorylation and Amyloid Neurotoxicity through GSK3β Inhibition.
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DOI：
10.1021/acschemneuro.6b00059
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发表时间：
2016-07-20
影响因子：
5
通讯作者：
Li QX
中科院分区：
文献类型：
--
作者：
Liang Z;Zhang B;Su WW;Williams PG;Li QX
阿尔茨海默病（AD）是世界范围内最常见的脑部疾病。异常的tau蛋白过度磷酸化和积累在神经元缠结的形成中起关键作用，与AD发病机制中的神经元功能障碍和认知障碍高度相关。糖原合成酶激酶-3 β（Glycogen synthase kinase-3β，GSK 3 β）是tau蛋白过度磷酸化的关键激酶。选择性抑制GSK 3 β是AD治疗的一个很有前途的策略。玉米须（CS，Zea mays L.）传统上被用作草药，最近因其潜在的认知益处而闻名。然而，迄今为止，CS的神经保护成分及其分子机制很少受到关注。作为我们针对一系列靶向AD tau蛋白病的激酶筛选植物化学物质的努力的一部分，我们发现CS提取物对GSK 3 β的抑制作用。随后的生物测定引导的分级分离导致分离和鉴定了两种6-C-糖基黄酮，异orientin（1）和3 '-甲氧基玉米素（2），其在体外对GSK 3 β具有选择性抑制作用。酶动力学和分子对接研究表明，1通过ATP非竞争性机制特异性抑制GSK 3 β，作为底物竞争性抑制剂。进一步的体外细胞研究表明，1有效地减弱了由GSK 3 β介导的tau磷酸化，并对β-淀粉样蛋白诱导的SH-SY 5 Y细胞中的tau过度磷酸化和神经毒性具有神经保护作用。C-糖基黄酮代表了新的先导候选物，具有开发AD植物药物的新作用机制。
Alzheimer’s disease (AD) is the most common brain disorder worldwide. The aberrant tau hyperphosphorylation and accumulation play a critical role in the formation of neurofibrillary tangles highly associated with neuronal dysfunction and cognitive impairment in AD pathogenesis. Glycogen synthase kinase-3β (GSK3β) is a key kinase responsible for tau hyperphosphorylation. Selective inhibition of GSK3β is a promising strategy in AD therapy. Corn silks (CS, Zea mays L.) have been traditionally used as a medicinal herb and recently noted for their potentially cognitive benefits. However, the neuroprotective components of CS and their molecular mechanism have received little attention to date. As part of our efforts screening phytochemicals against a broad panel of kinases targeting AD tauopathy, we found inhibition of GSK3β by CS extracts. Subsequent bioassay-guided fractionation led to the isolation and identification of two 6-C-glycosylflavones, isoorientin (1) and 3’-methoxymaysin (2), with selective inhibition against GSK3β in vitro. Enzyme kinetics and molecular docking studies demonstrated that 1 specifically inhibited GSK3β via an ATP noncompetitive mechanism, acting as a substrate competitive inhibitor of GSK3β. Further in vitro cellular studies demonstrated that 1 effectively attenuated tau phosphorylation mediated by GSK3β, and was neuroprotective against β-amyloid induced tau hyperphosphorylation and neurotoxicity in SH-SY5Y cells. The C-glycosylflavones represent new lead candidates with a novel mechanism of action for the development of AD phytopharmaceuticals.
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影响因子：
34.7
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.3109/09637486.2011.590797
发表时间：
2012-02-01
影响因子：
3.9
作者：
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通讯作者：
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