Therapeutic Intervention for Tauopathies

描述（由申请人提供）：由于未来20年内老年人口的巨大增长，阿尔茨海默病（AD）治疗方法的发展对美国至关重要。虽然对这种疾病的药物干预的大部分努力都是针对淀粉样蛋白的，但最近的证据表明，其他中心病理成分，tau，可能是一个必要的治疗靶点，特别是在已经有疾病症状的患者中。在这里，我们开发了一种独特的方法，可以快速分析tau水平，提供一种有效的方法来监测针对细胞内靶点（如tau）的化合物的功效。通过使用这种技术，我们建议1)鉴定改变tau蛋白的新化合物并开始确定其作用机制，2)更好地表征上调分子伴侣蛋白表达的药物，这是一种保护性级联反应，与病理tau蛋白的去除有关，也与其他与异常蛋白质积累相关的疾病有关。那些基于体外分析的最有希望的化合物将用于梅奥诊所独有的牛头病动物模型。

DESCRIPTION (provided by applicant): The development of therapeutics for Alzheimer's disease (AD) is of critical importance to the United States due to the enormous expected growth of the elderly population within the next 2 decades. While much of the effort toward pharmacological intervention in this disease has been directed toward amyloid, recent evidence has emerged suggesting that the other central pathological component, tau, may be a necessary therapeutic target, particularly in patients who already have disease symptoms. Here, we have developed a unique methodology that allows for the rapid analysis of tau levels, providing an efficient way to monitor the efficacy of compounds directed toward intracellular targets such as tau. By using this technique we propose to 1) identify new compounds that alter tau and begin to define their mechanism of action, and 2) better characterize drugs that upregulate molecular chaperone expression a protective cascade that has been implicated in the removal of pathological tau species and which has also been implicated in other diseases linked to abnormal protein accumulation. Those compounds with the greatest promise based on in vitro analyses will then be used in animal models for tauopathy that are exclusive to the Mayo Clinic.