Brain sterol dysregulation in sporadic AD and MCI: relationship to heme oxygenase-1.
Brain sterol dysregulation in sporadic AD and MCI: relationship to heme oxygenase-1.
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DOI：
10.1111/j.1471-4159.2009.06213.x
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发表时间：
2009-08
影响因子：
4.7
通讯作者：
Schipper HM
中科院分区：
文献类型：
--
作者：
Hascalovici JR;Vaya J;Khatib S;Holcroft CA;Zukor H;Song W;Arvanitakis Z;Bennett DA;Schipper HM
本研究的目的是确定衰老和阿尔茨海默病(AD)对脑胆固醇(CH)、CH前体和氧固醇稳态的影响。CH代谢改变和HO-1上调是阿尔茨海默病神经组织的特征。我们最近发现，HO-1的过表达通过增加肝X受体介导的CH外流抑制了总CH水平，并促进了培养的星形胶质细胞中氧固醇的形成。从死后人类额叶皮质提取脂质和蛋白质，这些人来自参加宗教秩序研究的散发性AD、轻度认知障碍(MCI)和无认知障碍(NCI；每组n=17)的受试者，这是一项正在进行的关于衰老和AD的临床病理研究。用ELISA法测定脑组织HO-1蛋白的表达，用气相色谱-质谱法(GC-MS)测定总胆红素、胆红素前体和相关的氧固醇量。通过多变量回归和非参数统计分析，确定激素水平与HO-1蛋白表达和临床/人口学变量之间的关系。MCI和AD患者大脑皮质CH值降低、氧固醇值升高、CH前体浓度升高与HO-1水平显著相关，而非NCI组与HO-1水平无相关性。特异性氧化甾醇与疾病状态相关，增加了神经病理负担、神经心理损害和年龄。基于目前的数据集和我们早期的体外工作，提出了一个模型，描述了MCI和AD中改变的类固醇稳态的补偿和去补偿状态。
The objective of this study was to ascertain the impact of aging and Alzheimer disease (AD) on brain cholesterol (CH), CH precursors and oxysterol homeostasis. Altered CH metabolism and up-regulation of heme oxygenase-1 (HO-1) are characteristic of AD-affected neural tissues. We recently determined that HO-1 over-expression suppresses total CH levels by augmenting liver X receptor-mediated CH efflux and enhances oxysterol formation in cultured astroglia. Lipids and proteins were extracted from post-mortem human frontal cortex derived from subjects with sporadic AD, mild cognitive impairment (MCI) and no cognitive impairment (NCI; n=17 per group) enrolled in the Religious Orders Study, an ongoing clinical-pathologic study of aging and AD. ELISA was used to quantify human HO-1 protein expression from brain tissue and GC-MS to quantify total CH, CH precursors and relevant oxysterols. The relationships of sterol/oxysterol levels to HO-1 protein expression and clinical/demographic variables were determined by multivariable regression and non-parametric statistical analyses. Decreased CH, increased oxysterol and increased CH precursors concentrations in the cortex correlated significantly with HO-1 levels in MCI and AD, but not NCI. Specific oxysterols correlated with disease state, increasing neuropathological burden, neuropsychological impairment and age. A model featuring compensated and de-compensated states of altered sterol homeostasis in MCI and AD are presented based on the current data set and our earlier in vitro work.
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影响因子：
8
作者：
Ferderbar, S.;Pereira, E. C.;Abdalla, D. S. P.
通讯作者：
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影响因子：
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