The oxysterol 27-hydroxycholesterol increases β-amyloid and oxidative stress in retinal pigment epithelial cells.
The oxysterol 27-hydroxycholesterol increases β-amyloid and oxidative stress in retinal pigment epithelial cells.
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DOI：
10.1186/1471-2415-10-22
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发表时间：
2010-09-13
影响因子：
2
通讯作者：
Ghribi O
中科院分区：
文献类型：
--
作者：
Dasari B;Prasanthi JR;Marwarha G;Singh BB;Ghribi O
阿尔茨海默病（AD）和年龄相关性黄斑变性（AMD）具有几个共同的病理特征，包括β-淀粉样蛋白（Aβ）肽积累、氧化损伤和细胞死亡。AD和AMD的原因尚不清楚，但一些研究表明胆固醇代谢紊乱是这些疾病的罪魁祸首。我们最近发现胆固醇氧化代谢产物27-羟基胆固醇（27-OHC）在人神经母细胞瘤SH-SY 5 Y细胞和器官型海马切片中引起AD样病理。然而，27-OHC也可能导致与AMD相关的病理标志的程度和机制尚不明确。在这项研究中，在ARPE-19细胞中测定了27-OHC对AMD相关病理学的影响。这些细胞具有与视网膜色素上皮细胞相关的结构和功能特性，视网膜色素上皮细胞是AMD过程中的目标。用0、10或25 μM 27-OHC处理ARPE-19细胞24小时。采用ELISA、Western印迹、免疫细胞化学和特异性试验评估Aβ肽、线粒体和内质网（ER）应激标志物、Ca 2+稳态、谷胱甘肽耗竭、活性氧（ROS）生成、炎症和细胞死亡水平。27-OHC剂量依赖性地增加Aβ肽的产生，增加ER应激特异性标志物caspase 12和gadd 153（也称为CHOP）的水平，降低线粒体膜电位，触发Ca 2+稳态失调，增加核因子κB（NFκB）和血红素加氧酶1（HO-1）的水平，这两种蛋白质由氧化应激激活。此外，27-OHC引起谷胱甘肽耗竭、ROS产生、炎症和促凋亡介导的细胞死亡。胆固醇代谢产物27-OHC对RPE细胞有毒性。这种氧固醇的有害作用范围从Aβ蓄积到氧化性细胞损伤。我们的研究结果表明，高水平的27-OHC可能是AMD和AD的共同致病因素。
Alzheimer's disease (AD) and age-related macular degeneration (AMD) share several pathological features including β-amyloid (Aβ) peptide accumulation, oxidative damage, and cell death. The causes of AD and AMD are not known but several studies suggest disturbances in cholesterol metabolism as a culprit of these diseases. We have recently shown that the cholesterol oxidation metabolite 27-hydroxycholesterol (27-OHC) causes AD-like pathology in human neuroblastoma SH-SY5Y cells and in organotypic hippocampal slices. However, the extent to which and the mechanisms by which 27-OHC may also cause pathological hallmarks related to AMD are ill-defined. In this study, the effects of 27-OHC on AMD-related pathology were determined in ARPE-19 cells. These cells have structural and functional properties relevant to retinal pigmented epithelial cells, a target in the course of AMD. ARPE-19 cells were treated with 0, 10 or 25 μM 27-OHC for 24 hours. Levels of Aβ peptide, mitochondrial and endoplasmic reticulum (ER) stress markers, Ca2+ homeostasis, glutathione depletion, reactive oxygen species (ROS) generation, inflammation and cell death were assessed using ELISA, Western blot, immunocytochemistry, and specific assays. 27-OHC dose-dependently increased Aβ peptide production, increased levels of ER stress specific markers caspase 12 and gadd153 (also called CHOP), reduced mitochondrial membrane potential, triggered Ca2+ dyshomeostasis, increased levels of the nuclear factor κB (NFκB) and heme-oxygenase 1 (HO-1), two proteins activated by oxidative stress. Additionally, 27-OHC caused glutathione depletion, ROS generation, inflammation and apoptotic-mediated cell death. The cholesterol metabolite 27-OHC is toxic to RPE cells. The deleterious effects of this oxysterol ranged from Aβ accumulation to oxidative cell damage. Our results suggest that high levels of 27-OHC may represent a common pathogenic factor for both AMD and AD.
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DOI：
10.1073/pnas.94.6.2642
发表时间：
1997-03-18
影响因子：
11.1
作者：
Kaltschmidt, B;Uherek, M;Kaltschmidt, C
通讯作者：
Kaltschmidt, C
影响因子：
4.7
作者：
Hascalovici JR;Vaya J;Khatib S;Holcroft CA;Zukor H;Song W;Arvanitakis Z;Bennett DA;Schipper HM
通讯作者：
Schipper HM
影响因子：
2
作者：
Joffre, Corinne;Leclere, Laurent;Creuzot-Garcher, Catherine
通讯作者：
Creuzot-Garcher, Catherine
影响因子：
6.5
作者：
Heverin, M;Meaney, S;Björkhem, I
通讯作者：
Björkhem, I
影响因子：
15.9
作者：
Björkhem, I
通讯作者：
Björkhem, I