基于代谢组学的阿尔茨海默病早期、最佳生物标志物的研究

The trend to increasing age in the world population pro?le has been accompanied by a steady rise in the prevalence of Alzheimer's disease (AD), which caused serious burden for both families and societies. Especially in china, a country grows old before grows rich. AD is an age-related neurodegenerative disease characterized by regressive dementia and the loss of cognitive abilities necessary for maintaining an independent lifestyle. The onset and development of AD are dormant, slowly and not clearly de?ned. when there are evident dementia symptoms, the best opportunity for treatment has already passed.Under this condition, it would be pretty significant to identify one or more early biomarkers and explore metabolic pathways and pathogenesis of AD, so that we could diagonose, intervene, prevent and cure the disease. Metabolomics is an emerging subject in recent year, it is concerned about the endogenous compounds, and is a strong technology that could simultaneously study small molecules compounds of biological system qualitatively and quantitatively. It also can amplify gene and protein expression of a small change in the metabolites. Based on multivariate analysis of complex biological pro?les, metabolomics has been successfully applied in biomarker screening. We make the metabonomics technology as platform, use UPLE-Q-TOF/MS to analyse blood samples and urine samples that collected from patients with AD. Our aim is to look for biomarkers and target that could early warning, diagnosis and treatment AD, and then explore metabolism pathway and pathogenesis of AD patients.

随着人口老龄化的加剧，老年痴呆（即阿尔茨海默病，简称AD）患者剧增，特别是"未富先老"的我国，对家庭和社会造成严重的负担。AD是一种以记忆损害和认知功能障碍为特征的神经退行性疾病，起病隐匿，进展缓慢，病因不明，当出现明显痴呆症状时，已失去治疗时机。如果能找到一种或几种早期、最佳生物标志物，探明代谢通路和发病机制，早期明确诊断，及时干预和治疗，使其不发生或延缓发生AD，以及提高治愈率具有重要意义。代谢组学是近几年新兴的一门组学，关注的是内源化合物，能够对生物体系中小分子化合物进行定性定量研究，将基因和蛋白质表达的微小变化在代谢物上放大，是筛选生物标志物的优势技术。本项目拟以代谢组学技术为平台，AD患者的血尿为样本，UPLE-Q-TOF/MS分析，寻找老年疾病AD早期预警、诊断、治疗的靶点或标志物，进而探索AD机体的代谢通路和发病机制。

阿尔茨海默病病因不明，致病机制尚不清楚，国内外对AD可能的生物标志物进行了大量研究，但仍没有获得一致的、易重复的、敏感特异的生物标志物。近年对AD患者血液和尿液代谢组学的研究几乎是一个空白。利用代谢组学技术平台，采用UPLC-Q-TOF/MS方法筛选阿尔茨海默病早期、敏感、特异的生物标志物，是研究的趋势和热点。因此，本项目寻找AD血尿标志物更具现实意义。. 从阿尔茨海默病患者血清中筛选出的锰、锂、铝、铜四种金属元素、弗林蛋白和维生素B1、B2、B6、B12可作为AD敏感可靠的早期生物标志物；从阿尔茨海默病患者尿中筛选出的N-丙烯酰基-甘氨酸、精氨基琥珀酸、脱硫生物素、L-乙酰肉碱、异丁酰基-L-肉碱、C16二氢神经鞘氨醇、壬二酸、雌二醇-1,3,5,(10),7-4-3,17α-二醇、L-天门冬氨酰-4-磷酸盐、L-谷氨酰胺、对甲酚-葡糖苷酸、本胆烷醇酮-葡糖苷酸、5-L-谷酰基甘氨酸、氨蝶呤、胞嘧啶核苷可作为AD敏感可靠的早期生物标志物；阿尔茨海默病转基因小鼠尿液中筛选出缬草烯醛、Cervonpyl-乙醇酰胺、壬二酸、3-羟基十四烷二酸，可作为AD潜在的生物标志物。该项目研究成果将为今后继续研究AD潜在的生物标志物提供可靠地理论依据。