Metabolomic Identification in Cerebrospinal Fluid of the Effects of High Dietary Cholesterol in a Rabbit Model of Alzheimer’s Disease
Metabolomic Identification in Cerebrospinal Fluid of the Effects of High Dietary Cholesterol in a Rabbit Model of Alzheimer’s Disease
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脑脊液代谢组学鉴定高膳食胆固醇对阿尔茨海默氏病兔模型的影响
DOI：
10.4172/2153-0769.1000109
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
O. Ghribi
中科院分区：
文献类型：
--
作者：
Q. Liu;E. Bingham;S. Twine;J. Geiger;O. Ghribi
研究背景阿尔茨海默病（Alzheimer's disease，AD）是最常见的神经退行性疾病，临床表现为认知功能障碍和痴呆。绝大多数病例为迟发性AD（LOAD），具有遗传异质性，并且偶尔发生。在兔饲料中添加2%胆固醇12周，可复制LOAD的神经病理改变。方法采用非靶向傅立叶变换离子回旋共振质谱技术，结合代谢组学方法和多元统计分析，研究胆固醇对12周脑脊液代谢物的影响。结果在6515个兔脑脊液中检测到的准确质量中，375个在不同时间点收集的样品之间显示出显著差异（p < 0.05）。对前95个的进一步分析（p < 0.01）揭示了在整个胆固醇处理过程中具有不同表达模式的四个代谢物簇。在胆固醇处理样品的12周中观察到大多数效应，而某些质量在8周时显示出短暂变化，但在12周时恢复到接近对照组的水平。治疗8周后开始变化的肿块可能代表与AD发展相关的大脑某些缺陷相关的早期代谢变化。推定的代谢物鉴定显示，胆固醇治疗8周后，某些磷酸化甘油酯和肽片段减少。结论高胆固醇负荷引起的脑脊液代谢紊乱具有特异性。特别是考虑到短肽片段的变化，这种影响可能是高胆固醇水平引起的大脑退化的结果。对这些肿块的进一步研究将有助于更好地了解与胆固醇相关的AD发展相关的代谢机制。这些肿块中的一些可用作诊断、预后或治疗诊断标志物的候选者。
Background Alzheimer’s disease (AD) is the most common neurodegenerative disorder, manifesting clinical symptoms of cognitive impairment and dementia. The vast majority of cases are late onset AD (LOAD), which are genetically heterogeneous and occur sporadically. The neuropathological changes of LOAD can be reproduced by supplementing a rabbit’s diet with 2% cholesterol for 12 weeks. Methods In the present study, a non-targeted Fourier transform ion cyclotron resonance mass spectrometry based metabolomics approach and multivariate statistics were used to survey the effect of cholesterol on cerebrospinal fluid metabolites over a 12 week time-course. Results Of the 6515 accurate masses detected in the rabbit CSF, 375 showed significant differences in intensity (p < 0.05) between samples collected at different time points. Further analysis of top 95 (p < 0.01) revealed four clusters of metabolites with different expression patterns throughout the course of the cholesterol treatment. The majority of effects were observed in 12 weeks of cholesterol treated samples, while certain masses showed transient changes at 8 weeks but returned back to near the levels of the controls at 12 weeks. The masses that started to change 8 weeks into the treatment may represent early metabolic changes linked to certain defects in the brain related to AD development. Putative metabolite identifications revealed certain phosphorylated glycerolipids and peptide fragments decreased after 8 weeks of cholesterol treatment. Conclusion This study showed that there are specific metabolic perturbations which occur in the CSF as a result of high cholesterol loading. Given the changes of short peptide fragments in particular, the effects are likely the consequence of brain degeneration caused by high cholesterol levels. Further investigations of these masses will lead to a greater understanding of the metabolic mechanisms associated with cholesterol-related AD development. Some of these masses may be used as candidates for the development of diagnostic, prognostic or theranostic markers.
将胆固醇与兔脑、海马器官切片和骨骼肌中类似阿尔茨海默病的病理联系起来的潜在机制。
DOI：
10.3233/jad-2008-15412
发表时间：
2008
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
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作者：
Ghribi,Othman
通讯作者：
Ghribi,Othman
影响因子：
7.4
作者：
Prasanthi, Jaya R. P.;Dasari, Bhanu;Marwarha, Gurdeep;Larson, Tyler;Chen, Xuesong;Geiger, Jonathan D.;Ghribi, Othman
通讯作者：
Ghribi, Othman