Inhibition of heparin-induced tau filament formation by phenothiazines, polyphenols, and porphyrins
Inhibition of heparin-induced tau filament formation by phenothiazines, polyphenols, and porphyrins
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DOI：
10.1074/jbc.m408714200
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发表时间：
2005-03-04
影响因子：
4.8
通讯作者：
Hasegawa, M
中科院分区：
文献类型：
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作者：
Taniguchi, S;Suzuki, N;Hasegawa, M
Tau 蛋白是神经元内丝状包涵体的主要成分，神经元内丝状包涵体构成了阿尔茨海默病和其他 tau 病的神经病理学特征。在家族性额颞叶痴呆中发现 tau 基因突变，证实 tau 蛋白功能障碍足以引起神经退行性和痴呆。在这里，我们测试了属于 9 个不同化学类别的 42 种化合物在体外抑制肝素诱导的 tau 蛋白组装成细丝的能力。几种吩噻嗪（亚甲基蓝、天青 A、天青 B 和奎纳克林芥末）、多酚（杨梅素、表儿茶素 5-没食子酸酯、棉布素和 2,3,4,2',4'-五羟基二苯甲酮）和卟啉铁脱氢卟啉 IX 抑制 tau 丝形成，IC50 值在低微摩尔范围内，评估如下：硫代黄素 S 荧光、电子显微镜和肌氨酰不溶性。在卟啉酞菁存在下观察到 tau 丝的分解。抑制 tau 丝组装的化合物也被发现能抑制 Abeta 原纤维的形成。生化分析揭示了在抑制性化合物存在的情况下可溶性寡聚 tau 蛋白的形成，表明这可能是抑制 tau 蛋白丝形成的机制。研究的化合物不会影响 tau 蛋白与微管相互作用的能力。肝素诱导的 tau 蛋白组装的小分子抑制剂的鉴定将成为开发基于机制的 tau 蛋白病疗法的起点。
Tau protein is the major component of the intraneuronal filamentous inclusions that constitute defining neuropathological characteristics of Alzheimer's disease and other tauopathies. The discovery of tau gene mutations in familial forms of frontotemporal dementia has established that dysfunction of the tau protein is sufficient to cause neurodegeneration and dementia. Here we have tested 42 compounds belonging to nine different chemical classes for their ability to inhibit heparin-induced assembly of tau into filaments in vitro. Several phenothiazines (methylene blue, azure A, azure B, and quinacrine mustard), polyphenols (myricetin, epicatechin 5-gallate, gossypetin, and 2,3,4,2',4'-penta-hydroxybenzophenone), and the porphyrin ferric dehydroporphyrin IX inhibited tau filament formation with IC50 values in the low micromolar range as assessed by thioflavin S fluorescence, electron microscopy, and Sarkosyl insolubility. Disassembly of tau filaments was observed in the presence of the porphyrin phthalocyanine. Compounds that inhibited tau filament assembly were also found to inhibit the formation of Abeta fibrils. Biochemical analysis revealed the formation of soluble oligomeric tau in the presence of the inhibitory compounds, suggesting that this may be the mechanism by which tau filament formation is inhibited. The compounds investigated did not affect the ability of tau to interact with microtubules. Identification of small molecule inhibitors of heparin-induced assembly of tau will form a starting point for the development of mechanismbased therapies for the tauopathies.