Inhibition of tau aggregation by a rosamine derivative that blocks tau intermolecular disulfide cross-linking
Inhibition of tau aggregation by a rosamine derivative that blocks tau intermolecular disulfide cross-linking
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DOI：
10.3109/13506129.2014.929103
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发表时间：
2014-09-01
影响因子：
5.5
通讯作者：
Kim, Yun Kyung
中科院分区：
文献类型：
--
作者：
Haque, Md. Mamunul;Kim, Dohee;Kim, Yun Kyung
异常tau聚集体被认为是神经毒性的，并且是包括阿尔茨海默病在内的多种神经退行性疾病的重要治疗靶标。越来越多的证据表明，tau分子间二硫键交联在产生tau寡聚体中是至关重要的，所述寡聚体用作高阶聚集体的构建块。在这里，我们报告说，一个小分子抑制剂，防止tau蛋白聚集通过阻断二硫键交联的tau蛋白寡聚体的产生。在测试的化合物中，具有温和硫醇反应性的玫瑰胺衍生物选择性地标记tau，并在体外有效地抑制寡聚化和纤维化过程。我们的数据表明，控制tau蛋白氧化状态可能是一种新的治疗策略，用于预防异常tau蛋白聚集。
Abnormal tau aggregates are presumed to be neurotoxic and are an important therapeutic target for multiple neurodegenerative disorders including Alzheimer's disease. Growing evidence has shown that tau intermolecular disulfide cross-linking is critical in generating tau oligomers that serve as a building block for higher-order aggregates. Here we report that a small molecule inhibitor prevents tau aggregation by blocking the generation of disulfide cross-linked tau oligomers. Among the compounds tested, a rosamine derivative bearing mild thiol reactivity selectively labeled tau and effectively inhibited oligomerization and fibrillization processes in vitro. Our data suggest that controlling tau oxidation status could be a new therapeutic strategy for prevention of abnormal tau aggregation.