Tauopathies are neurodegenerative diseases associated with accumulation of abnormal tau protein in the brain. Patient iPSC-derived neuronal cell models replicate disease-relevant phenotypes ex vivo that can be pharmacologically targeted for drug discovery. Here, we explored autophagy as a mechanism to reduce tau burden in human neurons and, from a small-molecule screen, identify the mTOR inhibitors OSI-027, AZD2014 and AZD8055. These compounds are more potent than rapamycin, and robustly downregulate phosphorylated and insoluble tau, consequently reducing tau-mediated neuronal stress vulnerability. MTORC1 inhibition and autophagy activity are directly linked to tau clearance. Notably, single-dose treatment followed by washout leads to a prolonged reduction of tau levels and toxicity for 12 days, which is mirrored by a sustained effect on mTORC1 inhibition and autophagy. This new insight into the pharmacodynamics of mTOR inhibitors in regulation of neuronal autophagy may contribute to development of therapies for tauopathies.

颅骨病是与脑中异常tau蛋白积聚有关的神经退行性疾病。患者iPSC衍生的神经元细胞模型离体复制与疾病相关的表型，该表型可以在药理上靶向药物发现。在这里，我们探讨了自噬作为减少人类神经元tau负担的机制，并从小分子筛选中鉴定了mTOR抑制剂OSI-027，AZD2014和AZD8055。这些化合物比雷帕霉素更有效，并能强烈下调磷酸化和不可溶的tau，从而降低tau介导的神经元应激易感性。MTORC1抑制和自噬活性与tau清除率直接相关。值得注意的是，单剂量治疗后再进行冲洗会导致tau水平和毒性持续降低12天，对mTORC1抑制和自噬的持续作用反映了这一点。有关mTOR抑制剂在调节神经元自噬中药效学的新见解可能有助于开发针对Tauopathies的疗法。