Drug Discovery Lab, Department of Neurology, University of California, Los Angeles, CA, USA; Gylys Lab, School of Nursing, University of California, Los Angeles, CA, USA.
Drug Discovery Lab, Department of Neurology, University of California, Los Angeles, CA, USA.
Biochem Biophys Res Commun. 2018 May 23;499(4):751-757. doi: 10.1016/j.bbrc.2018.03.209. Epub 2018 Apr 9.
Targeting of molecular pathways involved in the cell-to-cell propagation of pathological tau species is a novel approach for development of disease-modifying therapies that could block tau pathology and attenuate cognitive decline in patients with Alzheimer's disease and other tauopathies. We discovered cambinol through a screening effort and show that it is an inhibitor of cell-to-cell tau propagation. Our in vitro data demonstrate that cambinol inhibits neutral sphingomyelinase 2 (nSMase2) enzyme activity in dose response fashion, and suppresses extracellular vesicle (EV) production while reducing tau seed propagation. Our in vivo testing with cambinol shows that it can reduce the nSMase2 activity in the brain after oral administration. Our molecular docking and simulation analysis reveals that cambinol can target the DK-switch in the nSMase2 active site.
靶向病理性 tau 种在细胞间传播所涉及的分子途径是开发疾病修饰疗法的新方法，这种方法可以阻断 tau 病理学并减轻阿尔茨海默病和其他 tau 病患者的认知能力下降。我们通过筛选工作发现了 cambinol，并证明它是一种抑制细胞间 tau 传播的抑制剂。我们的体外数据表明，cambinol 以剂量反应的方式抑制中性鞘磷脂酶 2（nSMase2）酶活性，并抑制细胞外囊泡（EV）的产生，同时减少 tau 种子的传播。我们用 cambinol 进行的体内测试表明，它可以在口服后降低大脑中的 nSMase2 活性。我们的分子对接和模拟分析表明，cambinol 可以靶向 nSMase2 活性位点的 DK 开关。
