Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA.
MIND Institute, Center for Neurobiology of Learning and Memory, University of California, Irvine, CA, USA.
J Alzheimers Dis. 2019;71(1):119-140. doi: 10.3233/JAD-190408.
Age and Alzheimer's disease (AD) share some common features such as cognitive impairments, memory loss, metabolic disturbances, bioenergetic deficits, and inflammation. Yet little is known on how systematic shifts in metabolic networks depend on age and AD. In this work, we investigated the global metabolomic alterations in non-transgenic (NTg) and triple-transgenic (3xTg-AD) mouse brain hippocampus as a function of age by using untargeted Ultrahigh Performance Liquid Chromatography-tandem Mass Spectroscopy (UPLC-MS/MS). We observed common metabolic patterns with aging in both NTg and 3xTg-AD brains involved in energy-generating pathways, fatty acids oxidation, glutamate, and sphingolipid metabolism. We found age-related downregulation of metabolites from reactions in glycolysis that consumed ATP and in the TCA cycle, especially at NAD+/NADH-dependent redox sites, where age- and AD-associated limitations in the free NADH may alter reactions. Conversely, metabolites increased in glycolytic reactions in which ATP is produced. With age, inputs to the TCA cycle were increased including fatty acid β-oxidation and glutamine. Overall age- and AD-related changes were > 2-fold when comparing the declines of upstream metabolites of NAD+/NADH-dependent reactions to the increases of downstream metabolites (p = 10-5, n = 8 redox reactions). Inflammatory metabolites such as ceramides and sphingosine-1-phosphate also increased with age. Age-related decreases in glutamate, GABA, and sphingolipid were seen which worsened with AD genetic load in 3xTg-AD brains, possibly contributing to synaptic, learning- and memory-related deficits. The data support the novel hypothesis that age- and AD-associated metabolic shifts respond to NAD(P)+/NAD(P)H redox-dependent reactions, which may contribute to decreased energetic capacity.
年龄和阿尔茨海默病（AD）有一些共同的特征，如认知障碍、记忆丧失、代谢紊乱、生物能量缺陷和炎症。然而，人们对代谢网络的系统变化如何随年龄和 AD 而变化知之甚少。在这项工作中，我们通过非转基因（NTg）和三转基因（3xTg-AD）小鼠大脑海马的靶向和非靶向超高效液相色谱-串联质谱（UPLC-MS/MS）研究了随年龄变化的全局代谢组学改变。我们观察到 NTg 和 3xTg-AD 大脑中与能量生成途径、脂肪酸氧化、谷氨酸和神经酰胺代谢有关的共同代谢模式随年龄而变化。我们发现与年龄相关的代谢物下调与糖酵解和三羧酸循环（TCA）中消耗 ATP 的反应有关，特别是在 NAD+/NADH 依赖性氧化还原部位，其中与年龄和 AD 相关的自由 NADH 限制可能改变反应。相反，在产生 ATP 的糖酵解反应中，代谢物增加。随着年龄的增长，包括脂肪酸β氧化和谷氨酰胺在内的 TCA 循环输入增加。当比较 NAD+/NADH 依赖性反应的上游代谢物的下降与下游代谢物的增加时，与年龄和 AD 相关的变化超过 2 倍（p=10-5，n=8 个氧化还原反应）。炎症代谢物如神经酰胺和鞘氨醇-1-磷酸也随着年龄的增长而增加。在 3xTg-AD 大脑中，随着 AD 遗传负荷的增加，观察到谷氨酸、GABA 和神经酰胺的年龄相关性下降，这可能导致突触、学习和记忆相关缺陷。这些数据支持了一个新的假设，即年龄和 AD 相关的代谢变化与 NAD(P)+/NAD(P)H 氧化还原依赖性反应有关，这可能导致能量能力下降。
