Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2011 Jan 6;6(1):e15163. doi: 10.1371/journal.pone.0015163.
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.
METHODOLOGY/PRINCIPAL FINDINGS: 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.
许多研究表明，高水平的循环糖皮质激素是阿尔茨海默病（AD）的生化特征。这些应激激素可以增加疾病动物模型中类似 AD 的病理学数量。由于它们还上调了 5-脂氧合酶（5-LO），一种调节淀粉样蛋白β（Aβ）形成的酶，在本文中，我们检验了这样一个假设，即该酶促途径参与了糖皮质激素诱导的促淀粉样蛋白作用。
方法/主要发现：地塞米松孵育神经元细胞会导致 5-LO 活性和 Aβ形成的显著增加。相比之下，5-LO 的药理学抑制可防止地塞米松依赖性 Aβ水平升高。地塞米松挑战后，小鼠胚胎成纤维细胞对 Aβ形成有明显增加的反应。然而，当地塞米松与缺乏 5-LO 的成纤维细胞孵育时，这种作用被消除了。两组之间的糖皮质激素受体水平没有差异。最后，用地塞米松治疗野生型小鼠会导致内源性脑 Aβ水平显著增加，而缺乏 5-LO 的小鼠则可预防这种增加。
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作用。
