Therapeutic Intervention for Tauopathies

描述(由申请人提供)：阿尔茨海默病(AD)疗法的发展对美国至关重要，因为预计未来20年老年人口将大幅增长。虽然对这种疾病进行药物干预的大部分努力都是针对淀粉样蛋白的，但最近出现的证据表明，另一种中枢病理成分tau可能是必要的治疗靶点，特别是对已经有疾病症状的患者。在这里，我们开发了一种独特的方法，允许快速分析tau水平，提供了一种有效的方法来监控针对细胞内靶点的化合物的有效性，例如tau。通过使用这项技术，我们建议1)鉴定改变tau的新化合物，并开始定义它们的作用机制，2)更好地表征上调分子伴侣表达的药物，这种保护性级联已被认为与病理性tau物种的移除有关，也与其他与蛋白质异常积累有关的疾病有关。这些基于体外分析的最有希望的化合物将被用于梅奥诊所独有的相互作用的动物模型。

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.