Identifying new tau targeted therapeutics: a drug repurposing approach

描述（由申请人提供）： 由Ab肽构成的淀粉样斑块和由异常tau蛋白构成的神经元缠结定义了阿尔茨海默病的神经病理学。许多不同的研究支持淀粉样蛋白在阿尔茨海默病中的起始作用。然而，这些发现也清楚地表明，tau蛋白的存在是淀粉样蛋白介导的神经元功能障碍所必需的，并且病理性tau蛋白导致神经变性。此外，病理性tau，包括神经元缠结，表征冲击波诱导的创伤性脑损伤、慢性创伤性脑病和其他相关tau蛋白病的神经病理学。创伤性脑损伤在退伍军人中越来越普遍。与衰老相关的变化和脑损伤都显著增加了神经退行性痴呆症的风险。因此，我们必须开发能够快速弥合工作台和床边之间差距的治疗方法。开发tau介导的神经变性的药理学干预是本研究项目的长期目标。我们的药物发现策略采用综合方法，旨在加快药物再利用。我们先前发表的工作通过筛选1120种获批药物的文库来鉴定能够改善tau蛋白病转基因小鼠模型中tau蛋白病的单一经验证的化合物，从而证明了这些方法的有效性。我们现在建议将这种药物重新定位方法扩展到涵盖大多数具有临床使用史的药物（约5400种药物）的药物集合。该项目的目标是：确定化合物减少tau蛋白聚集在转基因C。在tau蛋白病的elegans模型中和在tau蛋白聚集的人细胞培养模型中进行;基于其CNS渗透对命中进行优先排序，并鉴定调节幼年小鼠中病理性tau蛋白的给药和给药途径;使用以上鉴定的新化合物干预有症状的tau蛋白病小鼠。这些研究的完成将揭示FDA批准的候选药物用作阿尔茨海默病和爆炸诱导的创伤性脑损伤的tau靶向治疗剂，为用于治疗tau蛋白病疾病的重新用途的批准药物的临床试验提供理由。

DESCRIPTION (provided by applicant): The amyloid plaques made of Ab peptide and neurofibrillary tangles made of abnormal tau protein define the neuropathology of Alzheimer's disease. Many diverse studies support an initiating role for amyloid in Alzheimer's disease. However, these findings also clearly demonstrate both that the presence of tau is required for amyloid mediated neuronal dysfunction and that pathological tau protein causes neurodegeneration. Furthermore, pathological tau, including neurofibrillary tangles, characterizes the neuropathology of blast induced traumatic brain injury, chronic traumatic encephalopathy, and other related tauopathies. Traumatic brain injury is increasingly prevalent in the Veteran population. Both aging related changes and brain injury dramatically increase the risk for neurodegenerative dementia disorders. Thus it is imperative we develop treatments that can quickly bridge the gap between bench and bedside. Development of pharmacological interventions for tau mediated neurodegeneration is the long-term goal of this research project. Our drug discovery strategy employs an integrated approach aimed at expediting drug repurposing. Our previously published work demonstrated the effectiveness of these methods by screening a library of 1120 approved drugs to identify a single validated compound capable of ameliorating tau pathology in a transgenic mouse model of tauopathy. We now propose to extend this drug repositioning approach to a drug collection spanning most of the drugs with a history of clinical use (~5400 drugs). The objectives of this project are to: Identify compounds reducing tau aggregation in a transgenic C. elegans model of tauopathy and in a human cell culture model of tau aggregation; Prioritize hits based on their CNS penetration and identify dosing and routes of administration that modulate pathological tau in young mice; Use novel compounds identified above to intervene in symptomatic tauopathy mice. Completion of these studies will reveal FDA approved candidate drugs for use as tau targeted therapeutics for both Alzheimer's disease and blast induced traumatic brain injury, providing justification for the clinical testing of repurposed approved drugs for treatment of tauopathy disorders.