Involvement of 5-lipoxygenase in the corticosteroid-dependent amyloid beta formation: in vitro and in vivo evidence.
Involvement of 5-lipoxygenase in the corticosteroid-dependent amyloid beta formation: in vitro and in vivo evidence.
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DOI：
10.1371/journal.pone.0015163
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发表时间：
2011-01-06
期刊：
影响因子：
3.7
通讯作者：
Praticò D
中科院分区：
文献类型：
--
作者：
Puccio S;Chu J;Praticò D
大量研究表明，高循环水平的糖皮质激素是阿尔茨海默病（AD）的生化特征。这些应激激素会增加动物模型中 AD 样病理的数量。由于它们还上调 5-脂氧合酶 (5-LO)（一种调节淀粉样蛋白 β (Aβ) 形成的酶），因此在本文中，我们测试了这一酶促途径参与糖皮质激素诱导的促淀粉样蛋白作用的假设。神经元细胞与地塞米松一起孵育导致 5-LO 活性和 Aβ 形成显着增加。相比之下，5-LO 的药理学抑制可防止地塞米松依赖性 Aβ 水平增加。地塞米松激发后，小鼠胚胎成纤维细胞的 Aβ 形成显着增加。然而，当地塞米松与基因缺陷 5-LO 的成纤维细胞一起孵育时，这种效应被消除。两组之间没有观察到糖皮质激素受体水平存在差异。最后，用地塞米松治疗野生型小鼠会导致内源性脑 Aβ 水平显着增加，而遗传性缺乏 5-LO 的小鼠则可以阻止这种情况的发生。这些发现表明 5-LO 在糖皮质激素诱导的大脑 AD 样淀粉样蛋白病理学中发挥功能性作用。
Numerous studies show that high circulating level of glucocorticosteroids is a biochemical characteristic of Alzheimer's disease (AD). These stress hormones can increase the amount of AD-like pathology in animal models of the disease. Since they also up-regulate the 5-Lipoxygenase (5-LO), an enzyme which modulates amyloid beta (Aβ) formation, in the present paper we tested the hypothesis that this enzymatic pathway is involved in the glucocorticoid-induced pro-amyloidotic effect. Incubation of neuronal cells with dexamethasone resulted in a significant increase in 5-LO activity and Aβ formation. By contrast, pharmacological inhibition of 5-LO prevented the dexamethasone-dependent increase in Aβ levels. Mouse embryonic fibroblasts responded with a significant increase in Aβ formation after dexamethasone challenge. However, this effect was abolished when dexamethasone was incubated with fibroblasts genetically deficient for 5-LO. No difference in the glucocorticoid receptor levels was observed between the two groups. Finally, treatment of wild type mice with dexamethasone resulted in a significant increase in endogenous brain Aβ levels, which was prevented in mice genetically lacking 5-LO. These findings suggest that 5-LO plays a functional role in the glucocorticoid-induced brain AD-like amyloid pathology.
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