The number of neurofibrillary tangles containing abnormal hyperphosphorylated tau protein correlates with the degree of dementia in Alzheimer's disease (AD). In addition, autophagosome accumulation and disturbance of autophagy, the process by which toxic aggregate proteins are degraded in the cytosol, are also found in AD models. These indicate that regulation of the autophagy-lysosome system may be a potential therapeutic target for AD. Activation of transcription factor EB (TFEB), a master regulator of autophagy-lysosome system gene transcription, reduces the amount of tau in APP mice. Here, to identify potential therapeutic compounds for AD, we performed two types of screening to determine pharmacologically active compounds that increase 1) neuronal viability in okadaic acid-induced tau hyperphosphorylation-related neurodegeneration models and 2) nuclear localization of TFEB in high-contents screening. Ouabain, a cardiac glycoside, was discovered as a common hit compound in both screenings. It also exhibited a significant protective effect in tau transgenic fly and mouse models in vivo. This work demonstrates that ouabain enhances activation of TFEB through inhibition of the mTOR pathway and induces downstream autophagy-lysosomal gene expression and cellular restorative properties. Therefore, therapeutic approaches using ouabain reduce the accumulation of abnormal toxic tau in vitro and in vivo.

阿尔茨海默氏病（AD）中含有异常高磷酸化tau蛋白的神经原纤维缠结的数量与痴呆程度相关。另外，在AD模型中也发现了自噬体的积累和自噬的干扰，自噬是有毒聚集蛋白在细胞质中降解的过程。这些表明自噬-溶酶体系统的调节可能是AD的潜在治疗靶标。转录因子EB（TFEB）的激活是自噬-溶酶体系统基因转录的主要调节因子，可降低APP小鼠中tau的含量。在这里，为了确定潜在的AD治疗化合物，我们进行了两种类型的筛选以确定增加1）冈田酸诱导的tau过度磷酸化相关的神经退行性模型中神经元生存力和2）TFEB在高含量筛选中的核定位的药理活性化合物。两次筛查均发现强心苷-哇巴因是常见的打击化合物。它还在体内的tau转基因蝇和小鼠模型中显示出显着的保护作用。这项工作表明哇巴因通过抑制mTOR途径增强TFEB的激活并诱导下游自噬-溶酶体基因表达和细胞修复特性。因此，使用哇巴因的治疗方法可减少体内和体外异常毒性tau的积累。两种筛选中均发现强心苷是常见的命中化合物。它还在体内的tau转基因蝇和小鼠模型中显示出显着的保护作用。这项工作表明哇巴因通过抑制mTOR途径增强TFEB的激活并诱导下游自噬-溶酶体基因表达和细胞修复特性。因此，使用哇巴因的治疗方法可减少体内和体外异常毒性tau的积累。两种筛选中均发现强心苷是常见的命中化合物。它还在体内的tau转基因蝇和小鼠模型中显示出显着的保护作用。这项工作表明哇巴因通过抑制mTOR途径增强TFEB的激活并诱导下游自噬-溶酶体基因表达和细胞修复特性。因此，使用哇巴因的治疗方法可减少体内和体外异常毒性tau的积累。