Department of Neuroscience, Central Clinical School, Monash University, The Alfred Hospital, Melbourne, VIC, 3004, Australia.
Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Parkville, VIC, 3052, Australia.
Metabolomics. 2021 Apr 19;17(5):42. doi: 10.1007/s11306-021-01793-4.
The mechanistic role of amyloid precursor protein (APP) in Alzheimer's disease (AD) remains unclear.
Here, we aimed to identify alterations in cerebral metabolites and metabolic pathways in cortex, hippocampus and serum samples from Tg2576 mice, a widely used mouse model of AD.
Metabolomic profilings using liquid chromatography-mass spectrometry were performed and analysed with MetaboAnalyst and weighted correlation network analysis (WGCNA).
Expressions of 11 metabolites in cortex, including hydroxyphenyllactate-linked to oxidative stress-and phosphatidylserine-lipid metabolism-were significantly different between Tg2576 and WT mice (false discovery rate < 0.05). Four metabolic pathways from cortex, including glycerophospholipid metabolism and pyrimidine metabolism, and one pathway (sulphur metabolism) from hippocampus, were significantly enriched in Tg2576 mice. Network analysis identified five pathways, including alanine, aspartate and glutamate metabolism, and mitochondria electron transport chain, that were significantly correlated with AD genotype.
Changes in metabolite concentrations and metabolic pathways are present in the early stage of APP pathology, and may be important for AD development and progression.
淀粉样前体蛋白（APP）在阿尔茨海默病（AD）中的作用机制仍不清楚。
本研究旨在鉴定 APP 转基因（Tg2576）小鼠脑皮质、海马组织及血清样本中代谢物和代谢途径的改变，Tg2576 小鼠是 AD 广泛应用的小鼠模型。
采用液相色谱-质谱联用技术进行代谢组学分析，并使用 MetaboAnalyst 和加权相关网络分析（WGCNA）进行分析。
Tg2576 与野生型（WT）小鼠皮质中 11 种代谢物的表达存在显著差异，包括与氧化应激相关的羟苯乳酸盐和与磷脂代谢相关的磷酸丝氨酸（假发现率<0.05）。皮质中有 4 条代谢途径，包括甘油磷脂代谢和嘧啶代谢，海马中有 1 条代谢途径（硫代谢）在 Tg2576 小鼠中显著富集。网络分析确定了 5 条与 AD 基因型显著相关的途径，包括丙氨酸、天冬氨酸和谷氨酸代谢以及线粒体电子传递链。
APP 病理早期存在代谢物浓度和代谢途径的改变，这些改变可能对 AD 的发生和发展很重要。
