Interaction between 24-hydroxycholesterol, oxidative stress, and amyloid-β in amplifying neuronal damage in Alzheimer's disease: three partners in crime
Interaction between 24-hydroxycholesterol, oxidative stress, and amyloid-β in amplifying neuronal damage in Alzheimer's disease: three partners in crime
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DOI：
10.1111/j.1474-9726.2011.00681.x
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发表时间：
2011-06-01
期刊：
影响因子：
7.8
通讯作者：
Poli, Giuseppe
中科院分区：
文献类型：
--
作者：
Gamba, Paola;Leonarduzzi, Gabriella;Poli, Giuseppe
迄今为止与阿尔茨海默病发病机制有关的所有三种胆固醇氧化产物，7-羟基胆固醇，24-羟基胆固醇和27-羟基胆固醇，通过上调CD36和β 1整合素受体的净表达和合成，显著增强淀粉样蛋白β (A β)与人类分化的神经细胞系（SK-N-BE和NT-2）的结合。然而，只有24-羟基胆固醇能显著增强A β(1-42)肽对这些细胞的促凋亡和促坏死作用；7-羟基胆固醇和27-羟基胆固醇，像未氧化的胆固醇一样，没有增强作用。24-羟基胆固醇在生理浓度（1 μ m）下的这种特殊行为取决于其对NADPH氧化酶依赖的活性氧（ROS）（主要是H2O2）的细胞内生成的强烈增强，以及由此导致的神经元细胞氧化还原平衡的损害（以GSSG/GSH比值衡量）。用抗氧化剂槲皮素或染料木素培养细胞可阻止24-羟基胆固醇的促氧化作用和A β诱导的坏死和凋亡的增强。因此，淀粉样斑块附近存在的24-羟基胆固醇似乎增强了大量A β与神经元质膜的粘附，然后通过局部增加ROS稳态水平来放大A β的神经毒性作用。该报告进一步支持了脑胆固醇代谢改变在阿尔茨海默病复杂发病机制中的主要参与。
P>All three cholesterol oxidation products implicated thus far in the pathogenesis of Alzheimer's disease, 7 beta-hydroxycholesterol, 24-hydroxycholesterol, and 27-hydroxycholesterol, markedly enhance the binding of amyloid-beta (A beta) to human differentiated neuronal cell lines (SK-N-BE and NT-2) by up-regulating net expression and synthesis of CD36 and beta 1-integrin receptors. However, only 24-hydroxycholesterol markedly potentiates the pro-apoptotic and pro-necrogenic effects of A beta(1-42) peptide on these cells: 7 beta-hydroxycholesterol and 27-hydroxycholesterol, like unoxidized cholesterol, show no potentiating effect. This peculiar behavior of 24-hydroxycholesterol at physiologic concentrations (1 mu m) depends on its strong enhancement of the intracellular generation of NADPH oxidase-dependent reactive oxygen species (ROS), mainly H2O2, and the consequent impairment of neuronal cell redox equilibrium, measured in terms of the GSSG/GSH ratio. Cell incubation with antioxidants quercetin or genistein prevents 24-hydroxycholesterol's pro-oxidant effect and potentiation of A beta-induced necrosis and apoptosis. Thus, the presence of 24-hydroxycholesterol in the close vicinity of amyloid plaques appears to enhance the adhesion of large amounts of A beta to the plasma membrane of neurons and then to amplify the neurotoxic action of A beta by locally increasing ROS steady-state levels. This report further supports a primary involvement of altered brain cholesterol metabolism in the complex pathogenesis of Alzheimer's disease.