摘要
阿尔茨海默病(AD)是一种渐进性的神经退行性疾病,其主要病理特征是淀粉样斑块的积累。然而,到目前为止并没有清楚地表明AD的生化改变。在这里,我们提出基于高分辨率质谱法的尿液代谢组学来用于描述转基因CRND8小鼠的代谢变化。在这种无创的方法中,尿液代谢组学揭示了AD小鼠模型发病早期的生化改变。凭借全面的代谢谱分析和多元统计分析,与同窝野生型小鼠相比,12周龄和18周龄的转基因小鼠的尿液样本集里被确定总共有73个微分代谢物,包括芳香族氨基酸代谢、克雷布斯循环和一碳代谢的扰动。特别有趣的是,观察到不同的色氨酸代谢如血清素途径的上调而犬尿氨酸途径的下调。同时, N-acetylvanilalanine和3-methoxytyrosine的累积表明芳香族L-氨基酸脱羧酶的缺乏。来源于芳香族氨基酸的代谢和通过甘氨酸结合反应的药物类II相代谢反应的微生物代谢产物也被突显,表明小鼠大脑的基因转变不仅改变基因型也扰乱肠道微生物。同时我们的研究表明,采用基于质谱的代谢组学和AD转基因小鼠模型结合的方法,可以为不同的代谢特征提供了新的证据。代谢途径的扰动可能对AD早期诊断和干预有深远的影响。
关键词: 阿尔茨海默病,质谱,代谢组学,无创分析,转基因CRND8,色氨酸代谢,尿液。
Current Alzheimer Research
Title:Urinary Metabolomics Reveals Alterations of Aromatic Amino Acid Metabolism of Alzheimer’s Disease in the Transgenic CRND8 Mice
Volume: 13 Issue: 7
Author(s): Zhi Tang, Liangfeng Liu, Yongle Li, Jiyang Dong, Min Li, Jiandong Huang, Shuhai Lin, Zongwei Cai
Affiliation:
关键词: 阿尔茨海默病,质谱,代谢组学,无创分析,转基因CRND8,色氨酸代谢,尿液。
摘要: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, with amyloid plaques accumulation as the key feature involved in its pathology. To date, however, the biochemical changes in AD have not been clearly characterized. Here, we present that urinary metabolomics based on high resolution mass spectrometry was employed for delineation of metabolic alterations in transgenic CRND8 mice. In this noninvasive approach, urinary metabolome reveals the biochemical changes in early onset of this AD mouse model. In virtue of comprehensive metabolite profiling and multivariate statistical analysis, a total of 73 differential metabolites of urine sample sets was identified in 12-week and 18-week transgenic mice compared to wild-type littermates, covering perturbations of aromatic amino acid metabolism, the Krebs cycle and one-carbon metabolism. Of particular interest is that divergent tryptophan metabolism, such as upregulation of serotonin pathway while downregulation of kynurenine pathway, was observed. Meanwhile, the accumulation of both N-acetylvanilalanine and 3-methoxytyrosine indicated aromatic L-amino acid decarboxylase deficiency. And the microbial metabolites derived from aromatic amino acid metabolism and drug-like phase II metabolic response via the glycine conjugation reactions were also highlighted, indicating that genetic modification in mouse brain not only alters genotype but also perturbs the gut microbiome. Together, our study demonstrated that the integrative approach employing mass spectrometry-based metabolomics and a transgenic mouse model for AD may provide new evidence for distinct metabolic signatures. The perturbations of metabolic pathways may have far-reaching implications for early diagnosis and intervention in AD.
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Zhi Tang, Liangfeng Liu, Yongle Li, Jiyang Dong, Min Li, Jiandong Huang, Shuhai Lin, Zongwei Cai , Urinary Metabolomics Reveals Alterations of Aromatic Amino Acid Metabolism of Alzheimer’s Disease in the Transgenic CRND8 Mice, Current Alzheimer Research 2016; 13 (7) . https://dx.doi.org/10.2174/1567205013666160129095340
DOI https://dx.doi.org/10.2174/1567205013666160129095340 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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