In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice
In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice
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DOI：
10.3233/jad-190465
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发表时间：
2020-01-01
影响因子：
4
通讯作者：
Moe, James G.
中科院分区：
文献类型：
--
作者：
Davidowitz, Eliot J.;Krishnamurthy, Pavan K.;Moe, James G.
研究表明，tau寡聚体通过种子、tau错误折叠和聚集将tau病理从患病神经元传递到健康神经元，这被认为在阿尔茨海默病(AD)和相关tauopathy的进展中发挥了重要作用。为了开发一种治疗AD和相关tau病的小分子药物，我们开发了体外和细胞实验来选择抑制tau聚集的第一步的分子，tau聚集的第一步是tau自身结合成低聚物。一种优化的先导化合物的体内验证研究是在htau小鼠模型中独立进行的，该模型表达了与AD无关的遗传的tau突变的人类tau亚型。接受治疗的小鼠没有表现出任何与该化合物相关的不良事件。铅化合物显著降低了自结合的tau和总的和磷酸化的不溶性tau聚集体的水平。剂量反应与大脑中化合物的水平呈线性关系。对雄性htau小鼠进行了验证性研究，给出了一致的结果。结果验证了我们的筛选方法，通过使用选择和优化的先导化合物，靶向tau自结合可以抑制整个tau聚集途径，其活性从体外和细胞检测转化为tau聚集的体内模型。
Tau oligomers have been shown to transmit tau pathology from diseased neurons to healthy neurons through seeding, tau misfolding, and aggregation that is thought to play an influential role in the progression of Alzheimer's disease (AD) and related tauopathies. To develop a small molecule therapeutic for AD and related tauopathies, we have developed in vitro and cellular assays to select molecules inhibiting the first step in tau aggregation, the self-association of tau into oligomers. In vivo validation studies of an optimized lead compound were independently performed in the htau mouse model of tauopathy that expresses the human isoforms of tau without inherited tauopathy mutations that are irrelevant to AD. Treated mice did not show any adverse events related to the compound. The lead compound significantly reduced the level of self-associated tau and total and phosphorylated insoluble tau aggregates. The dose response was linear with respect to levels of compound in the brain. A confirmatory study was performed with male htau mice that gave consistent results. The results validated our screening approach by showing that targeting tau self-association can inhibit the entire tau aggregation pathway by using the selected and optimized lead compound whose activity translated from in vitro and cellular assays to an in vivo model of tau aggregation.