Hepta-Histidine Inhibits Tau Aggregation
Hepta-Histidine Inhibits Tau Aggregation
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DOI：
10.1021/acschemneuro.1c00164
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发表时间：
2021-07-28
影响因子：
5
通讯作者：
Okazawa, Hitoshi
中科院分区：
文献类型：
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作者：
Kondo, Kanoh;Ikura, Teikichi;Okazawa, Hitoshi
Tau聚集是tau蛋白病如额颞叶变性和进行性核上性麻痹以及阿尔茨海默病的中心标志，并且它已成为治疗开发的靶标。在此，我们意外地发现七组氨酸（7 H），Ku 70和亨廷顿蛋白之间相互作用的抑制剂，在体外抑制Tau-R3肽的聚集。将来自达特蛋白的转录反式激活因子（达特）序列（YGRKKRRQRRR）添加至7 H增加了其对细胞的渗透性，并且达特-7 H处理携带Tau或APP突变的iPS细胞衍生的神经元抑制Tau磷酸化。这些结果表明，7 H是一个有前途的先导化合物，用于开发抗聚集药物对Tau相关的神经退行性疾病，包括阿尔茨海默病（AD）。
Tau aggregation is a central hallmark of tauopathies such as frontotemporal lobar degeneration and progressive supranuclear palsy as well as of Alzheimer's disease, and it has been a target for therapeutic development. Herein, we unexpectedly found that hepta-histidine (7H), an inhibitor of the interaction between Ku70 and Huntingtin proteins, suppresses aggregation of Tau-R3 peptides in vitro. Addition of the trans-activator of transcription (TAT) sequence (YGRKKRRQRRR) derived from the TAT protein to 7H increased its permeability into cells, and TAT-7H treatment of iPS cell-derived neurons carrying Tau or APP mutations suppressed Tau phosphorylation. These results indicate that 7H is a promising lead compound for developing anti-aggregation drugs against Tau-related neurodegenerative diseases including Alzheimer's disease (AD).