Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan; Department of Aging and Dementia (DAD), Faculty of Medical Sciences, University of Fukui, Fukui, Japan; Life Science Innovation Center, University of Fukui, Fukui, Japan.
Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan; Department of Aging and Dementia (DAD), Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
Neurobiol Aging. 2020 May;89:41-54. doi: 10.1016/j.neurobiolaging.2019.12.009. Epub 2019 Dec 16.
Neurofibrillary tangles, one of the pathological hallmarks of Alzheimer's disease, consist of highly phosphorylated tau proteins. Tau protein binds to microtubules and is best known for its role in regulating microtubule dynamics. However, if tau protein is phosphorylated by activated major tau kinases, including glycogen synthase kinase 3β or cyclin-dependent kinase 5, or inactivated tau phosphatase, including protein phosphatase 2A, its affinity for microtubules is reduced, and the free tau is believed to aggregate, thereby forming neurofibrillary tangles. We previously reported that pitavastatin decreases the total and phosphorylated tau protein using a cellular model of tauopathy. The reduction of tau was considered to be due to Rho-associated coiled-coil protein kinase (ROCK) inhibition by pitavastatin. ROCK plays important roles to organize the actin cytoskeleton, an expected therapeutic target of human disorders. Several ROCK inhibitors are clinically applied to prevent vasospasm postsubarachnoid hemorrhage (fasudil) and for the treatment of glaucoma (ripasudil). We have examined the effects of ROCK inhibitors (H1152, Y-27632, and fasudil [HA-1077]) on tau protein phosphorylation in detail. A human neuroblastoma cell line (M1C cells) that expresses wild-type tau protein (4R0N) by tetracycline-off (TetOff) induction, primary cultured mouse neurons, and a mouse model of tauopathy (rTG4510 line) were used. The levels of phosphorylated tau and caspase-cleaved tau were reduced by the ROCK inhibitors. Oligomeric tau levels were also reduced by ROCK inhibitors. After ROCK inhibitor treatment, glycogen synthase kinase 3β, cyclin-dependent kinase 5, and caspase were inactivated, protein phosphatase 2A was activated, and the levels of IFN-γ were reduced. ROCK inhibitors activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Collectively, these results suggest that ROCK inhibitors represent a viable therapeutic route to reduce the pathogenic forms of tau protein in tauopathies, including Alzheimer's disease.
神经原纤维缠结是阿尔茨海默病的病理标志之一，由高度磷酸化的 tau 蛋白组成。Tau 蛋白与微管结合，以其调节微管动力学的作用而闻名。然而，如果 tau 蛋白被激活的主要 tau 激酶（包括糖原合酶激酶 3β或周期依赖性激酶 5）或失活的 tau 磷酸酶（包括蛋白磷酸酶 2A）磷酸化，其与微管的亲和力降低，游离的 tau 被认为会聚集，从而形成神经原纤维缠结。我们之前报道过，匹伐他汀通过 tau 病的细胞模型降低总 tau 和磷酸化 tau 蛋白。tau 的减少被认为是由于匹伐他汀抑制 Rho 相关卷曲螺旋蛋白激酶（ROCK）。ROCK 在组织肌动蛋白细胞骨架中发挥重要作用，这是人类疾病的预期治疗靶点。几种 ROCK 抑制剂已在临床上用于预防蛛网膜下腔出血后血管痉挛（法舒地尔）和治疗青光眼（利匹司他）。我们详细研究了 ROCK 抑制剂（H1152、Y-27632 和法舒地尔[HA-1077]）对 tau 蛋白磷酸化的影响。使用人神经母细胞瘤细胞系（通过四环素关闭（TetOff）诱导表达野生型 tau 蛋白（4R0N）的 M1C 细胞）、原代培养的小鼠神经元和 tau 病的小鼠模型（rTG4510 系）。ROCK 抑制剂降低了磷酸化 tau 和半胱天冬酶切割的 tau 的水平。寡聚 tau 水平也被 ROCK 抑制剂降低。ROCK 抑制剂处理后，糖原合酶激酶 3β、周期依赖性激酶 5 和半胱天冬酶失活，蛋白磷酸酶 2A 被激活，IFN-γ 水平降低。ROCK 抑制剂激活自噬和蛋白酶体途径，这被认为对 tau 蛋白的降解很重要。综上所述，这些结果表明 ROCK 抑制剂是减少包括阿尔茨海默病在内的 tau 病中 tau 蛋白致病形式的可行治疗途径。
