Bahety Priti, Tan Yee Min, Hong Yanjun, Zhang Luqi, Chan Eric Chun Yong, Ee Pui-Lai Rachel
Department of Pharmacy, National University of Singapore, Singapore, Republic of Singapore.
PLoS One. 2014 Feb 27;9(2):e90123. doi: 10.1371/journal.pone.0090123. eCollection 2014.
Despite the significant amount of work being carried out to investigate the therapeutic potential of docosahexaenoic acid (DHA) in Alzheimer's disease (AD), the mechanism by which DHA affects amyloid-β precursor protein (AβPP)-induced metabolic changes has not been studied.
To elucidate the metabolic phenotypes (metabotypes) associated with DHA therapy via metabonomic profiling of an AD cell model using gas chromatography time-of-flight mass spectrometry (GC/TOFMS).
The lysate and supernatant samples of CHO-wt and CHO-AβPP695 cells treated with DHA and vehicle control were collected and prepared for GC/TOFMS metabonomics profiling. The metabolic profiles were analyzed by multivariate data analysis techniques using SIMCA-P+ software.
Both principal component analysis and subsequent partial least squares discriminant analysis revealed distinct metabolites associated with the DHA-treated and control groups. A list of statistically significant marker metabolites that characterized the metabotypes associated with DHA treatment was further identified. Increased levels of succinic acid, citric acid, malic acid and glycine and decreased levels of zymosterol, cholestadiene and arachidonic acid correlated with DHA treatment effect. DHA levels were also found to be increased upon treatment.
Our study shows that DHA plays a role in mitigating AβPP-induced impairment in energy metabolism and inflammation by acting on tricarboxylic acid cycle, cholesterol biosynthesis pathway and fatty acid metabolism. The perturbations of these metabolic pathways by DHA in CHO-wt and CHO-AβPP695 cells shed further mechanistic insights on its neuroprotective actions.
尽管在研究二十二碳六烯酸（DHA）治疗阿尔茨海默病（AD）的潜在疗效方面已开展了大量工作，但DHA影响淀粉样前体蛋白（AβPP）诱导的代谢变化的机制尚未得到研究。
通过使用气相色谱飞行时间质谱（GC/TOFMS）对AD细胞模型进行代谢组学分析，以阐明与DHA治疗相关的代谢表型（代谢型）。
收集用DHA及溶剂对照处理的CHO-wt和CHO-AβPP695细胞的裂解物和上清液样本，并制备用于GC/TOFMS代谢组学分析。使用SIMCA-P+软件通过多变量数据分析技术分析代谢谱。
主成分分析及随后的偏最小二乘判别分析均揭示了与DHA处理组和对照组相关的不同代谢物。进一步确定了一系列表征与DHA治疗相关代谢型的具有统计学意义的标记代谢物。琥珀酸、柠檬酸、苹果酸和甘氨酸水平升高以及酵母甾醇、胆二烯和花生四烯酸水平降低与DHA治疗效果相关。还发现处理后DHA水平升高。
我们的研究表明，DHA通过作用于三羧酸循环、胆固醇生物合成途径和脂肪酸代谢，在减轻AβPP诱导的能量代谢和炎症损伤中发挥作用。DHA对CHO-wt和CHO-AβPP695细胞中这些代谢途径的扰动为其神经保护作用提供了进一步的机制见解。
