Tauopathies are neurodegenerative diseases that manifest with intracellular accumulation and aggregation of tau protein. These include Pick’s disease, progressive supranuclear palsy, corticobasal degeneration and argyrophilic grain disease, where tau is believed to be the primary disease driver, as well as secondary tauopathies, such as Alzheimer’s disease. There is a need to develop effective pharmacological therapies. Here we tested >1,400 clinically approved compounds using transgenic zebrafish tauopathy models. This revealed that carbonic anhydrase (CA) inhibitors protected against tau toxicity. CRISPR experiments confirmed that CA depletion mimicked the effects of these drugs. CA inhibition promoted faster clearance of human tau by promoting lysosomal exocytosis. Importantly, methazolamide, a CA inhibitor used in the clinic, also reduced total and phosphorylated tau levels, increased neuronal survival and ameliorated neurodegeneration in mouse tauopathy models at concentrations similar to those seen in people. These data underscore the feasibility of in vivo drug screens using zebrafish models and suggest serious consideration of CA inhibitors for treating tauopathies.

tau 蛋白病是神经退行性疾病，表现为 tau 蛋白的细胞内积累和聚集。这些疾病包括 Pick 病、进行性核上性麻痹、皮质基底节变性和嗜银颗粒病，其中 tau 被认为是主要的疾病驱动因素，以及继发性 tau 蛋白病，例如阿尔茨海默病。需要开发有效的药物治疗。在这里，我们使用转基因斑马鱼 tau 病模型测试了 >1,400 种临床批准的化合物。这表明碳酸酐酶 （CA） 抑制剂可防止 tau 毒性。CRISPR 实验证实 CA 耗竭模拟了这些药物的作用。CA 抑制通过促进溶酶体胞吐作用促进人 tau 的更快清除。重要的是，甲唑胺是一种临床上使用的 CA 抑制剂，在与人类相似的浓度下，小鼠 tau 蛋白病模型中的 tau 蛋白总水平和磷酸化 tau 蛋白水平也降低了总蛋白和磷酸化 tau 蛋白水平，提高了神经元存活率，并改善了神经退行性变。这些数据强调了使用斑马鱼模型进行体内药物筛选的可行性，并建议认真考虑 CA 抑制剂治疗 tau 蛋白病。