Pitavastatin decreases tau levels via the inactivation of Rho/ROCK
Pitavastatin decreases tau levels via the inactivation of Rho/ROCK
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DOI：
10.1016/j.neurobiolaging.2011.10.020
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发表时间：
2012-10-01
影响因子：
4.2
通讯作者：
Kuriyama, Masaru
中科院分区：
文献类型：
--
作者：
Hamano, Tadanori;Yen, Shu-Hui;Kuriyama, Masaru
流行病学研究表明，长期服用他汀类药物可以降低患阿尔茨海默病的风险。他汀类药物通过降低类异戊二烯中间体的浓度而具有多效性作用。虽然一些研究表明，他汀类药物可以降低淀粉样β蛋白水平，但很少有关于他汀类药物和tau之间相互作用的报道。我们在这里报告，匹伐他汀减少总的和磷酸化的tau蛋白水平的tau蛋白病变的细胞模型，并在原代神经元培养。由匹伐他汀引起的降低可通过加入甲羟戊酸或焦磷酸香叶基香叶基酯来逆转。包括RhoA在内的小G蛋白的成熟被匹伐他汀破坏，糖原合成酶激酶3 β（GSK 3 β）（一种主要的tau激酶）的活性也被破坏。毒素A、小G蛋白糖基化抑制剂和Rho激酶（ROCK）抑制剂降低磷酸化tau水平。Rho激酶抑制剂也使糖原合成酶激酶3 β失活。尽管匹伐他汀减少tau蛋白的机制需要进一步研究，但本报告揭示了tau蛋白病的可能治疗方法。(c)2012 Elsevier Inc. All rights reserved.
Epidemiological studies have shown that long-term treatment with statins decreases the risk of developing Alzheimer's disease. Statins have pleiotropic effects by lowering the concentration of isoprenoid intermediates. Although several studies have shown that statins may reduce amyloid beta protein levels, there have been few reports on the interaction between statins and tau. We report here that pitavastatin reduces total and phosphorylated tau levels in a cellular model of tauopathy, and in primary neuronal cultures. The decrease caused by pitavastatin is reversed by the addition of mevalonate, or geranylgeranyl pyrophosphate. The maturation of small G proteins, including RhoA was disrupted by pitavastatin, as was the activity of glycogen synthase kinase 3 beta (GSK3 beta), a major tau kinase. Toxin A, inhibitor of glycosylation of small G proteins, and Rho kinase (ROCK) inhibitor decreased phosphorylated tau levels. Rho kinase inhibitor also inactivated glycogen synthase kinase 3 beta. Although the mechanisms responsible for the reduction in tau protein by pitavastatin require further examination, this report sheds light on possible therapeutic approaches to tauopathy. (c) 2012 Elsevier Inc. All rights reserved.