Changing the energy substrate balance: Does APOE2 promote glucose usage to protect from Alzheimer's Disease?

改变能量底物平衡：APOE2 是否会促进葡萄糖的使用以预防阿尔茨海默病？

• 批准号: 10378535
• 负责人: Lance Allen Johnson
• 金额: $ 43.7万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378535
• 关键词: Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Animals; Apolipoprotein E; Astrocytes; Basal metabolic rate; Biochemical; Biochemical Pathway; Biological; Biological Markers; Brain; Carbohydrates; Carbon Dioxide; Cell Line; Cells; Cerebrum; Clinical; Coculture Techniques; Cognitive; Data; Data Analyses; Dementia; Development; Disease; Equilibrium; Fatty Acids; Future; Gene Expression Profiling; Genes; Genetic; Genotype; Glucose; Human; Impaired cognition; In Vitro; Individual; Intervention; Knowledge; Late Onset Alzheimer Disease; Lead; Link; Lipids; Lipoproteins; Measures; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolism; Mus; Neuronal Dysfunction; Neurons; Obesity; Oxides; Pathway interactions; Pattern; Peripheral; Pharmacology; Population; Prevention; Protein Isoforms; Reporting; Rest; Severities; Symptoms; System; Testing; Tissues; Tracer; Translating; age related; apolipoprotein E-4; base; brain tissue; design; energy balance; experimental study; fatty acid oxidation; fluorodeoxyglucose positron emission tomography; genetic risk factor; genome-wide; glucose metabolism; glucose transport; glucose uptake; high risk; in vivo; innovation; insight; metabolic profile; metabolomics; mouse model; multiple omics; neuronal survival; neuroprotection; novel; oxidation; precision genetics; preference; prevent; relating to nervous system; respiratory; response; stable isotope; therapeutic target; transcriptomics; translational study; uptake

Metabolic dysfunction, as in the case of obesity, contributes to the development of several age-related diseases, including Alzheimer’s disease (AD). Apolipoprotein E (apoE) is a critical component of circulating lipoproteins found both in the periphery and brain, and the APOE gene encodes three major isoforms in the human population: E2, E3, and E4. E4 is the most significant genetic risk factor for sporadic AD, while E2 is protective. Like obesity, the E4 isoform is also associated with an increased risk of AD. Paradoxically, mice and humans with E4 have an increased risk of AD despite having reduced adiposity, while those with E2 are protected from AD despite increased adiposity. Our preliminary findings in mice suggest that these two factors – obesity and apoE – may be linked by a unifying biological mechanism related to energy substrate preference, and have broad implications for the prevention and personalized (genetic) treatment of AD. Our central hypothesis is that the apoE isoforms differentially shift the Randle cycle balance: E2 in favor of glucose, E4 in favor of FA. Specifically, we hypothesize that E2 exerts its neuroprotective effects through a metabolic preference for glucose utilization at the expense of fatty acid oxidation. To test the hypothesis that E2 affords neuroprotection by decreasing fatty acid oxidation and increasing glucose utilization, we will quantitatively track substrate entry and metabolism through the unique precursor-product “tracing” afforded by Stable Isotope Resolved Metabolomics (SIRM). We will then use a multi-omics approach to integrate SIRM results with transcriptomic profiling of human apoE expressing mice and cells in order to identify the specific metabolic pathways altered by E2 expression in both the brain and periphery. Finally, we will translate our findings by measuring basal metabolic rates in E2-, E3- and E4-expressing individuals at rest, and during a cognitive challenge. Using O2 and CO2 recordings, we will calculate the respiratory exchange ratio (RER), which reflects the ratio of carbohydrate/lipid oxidation, across each trial. Analyzing these data based on APOE status will provide a new understanding of substrate utilization in E2+ individuals, and offer insight into potential apoE effects on peripheral and neural energy responses. If successful, this proposal will provide novel targets by characterizing the neuroprotective metabolic profile of E2 individuals and designing future therapies to mimic these effects. Enhancing cerebral metabolism by making “E2-like” changes to energy balance could have great impact in preventing or delaying the onset of AD.

代谢功能障碍，例如肥胖症，有助于几个与年龄有关的发展 包括阿尔茨海默氏病（AD）在内的疾病。载脂蛋白E（APOE）是循环的关键组成部分 脂蛋白在周围和大脑中均发现，APOE基因编码三个主要同工型。 人口：E2，E3和E4。 E4是零星AD的最重要的遗传危险因素，而E2是 保护的。像对象一样，E4同工型也与AD风险增加有关。矛盾的是小鼠 E4患者的肥胖降低风险增加，而具有E2的人则是 免受AD任务的保护增加了肥胖。我们在小鼠中的初步发现表明这两个因素 - 肥胖和apoE - 可以通过与能量底物偏好相关的统一生物学机制联系在一起 并对AD的预防和个性化（遗传）处理具有广泛的影响。我们的中心 假设是APOE同工型不同地改变了Randle循环平衡：E2支持葡萄糖，E4 IN FA的青睐。特别是，我们假设E2通过代谢执行其神经保护作用 以脂肪酸氧化为代价，偏爱葡萄糖利用。测试E2提供的假设 神经保护通过减少脂肪酸氧化并增加葡萄糖利用，我们将定量跟踪 通过稳定同位素提供的独特前体产品“跟踪”的底物进入和代谢 已解决的代谢组学（SIRM）。然后，我们将使用多摩学方法将SIRM结果与 表达小鼠和细胞的人apoe的转录组分析，以识别特定的代谢 大脑和周围的E2表达改变的途径。最后，我们将通过 在静止和认知期间测量E2-，E3-和E4表达E4表达的个体的基本代谢率 挑战。使用O2和CO2记录，我们将计算反映的呼吸交换比（RER）（RER） 在每个试验中，碳水化合物/脂质氧化的比率。根据APOE状态分析这些数据将 对E2+个体中的底物利用提供了新的了解，并提供了对潜在APOE的见解 对周围和神经能量反应的影响。如果成功，该建议将通过 表征E2个体的神经保护性代谢谱并设计未来的疗法 这些影响。通过对能量平衡进行“类似E2的”变化来增强大脑代谢 影响或延迟AD发作的影响。