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

代谢功能障碍，如在肥胖症的情况下，有助于发展几个年龄相关的 疾病，包括阿尔茨海默病（AD）。载脂蛋白E（apoE）是循环系统的关键组分， APOE基因编码外周和大脑中的三种主要亚型， 人群：E2、E3和E4。E4是散发性AD最重要的遗传危险因素，而E2是 保护性的与肥胖一样，E4亚型也与AD风险增加有关。巧合的是，老鼠 尽管肥胖减少，但具有E4的人患AD的风险增加，而具有E2的人 尽管肥胖增加，但仍能防止AD。我们在小鼠身上的初步发现表明，这两个因素 - 肥胖和apoE -可能通过与能量底物偏好相关的统一生物学机制联系在一起， 并且对AD的预防和个性化（遗传）治疗具有广泛的意义。我们的中央 一种假说是apoE亚型不同地改变了Randle循环平衡：E2有利于葡萄糖，E4有利于葡萄糖， 喜欢FA。具体来说，我们假设E2通过代谢途径发挥其神经保护作用。 以脂肪酸氧化为代价优先利用葡萄糖。为了验证E2提供了 通过减少脂肪酸氧化和增加葡萄糖利用的神经保护，我们将定量跟踪 通过稳定同位素提供的独特的底物-产物“示踪”，底物进入和代谢 解析代谢组学（SIRM）。然后，我们将使用多组学方法将SIRM结果与 表达人apoE的小鼠和细胞的转录组学分析，以鉴定特定的代谢产物 E2在大脑和外周的表达改变了神经通路。最后，我们将把我们的发现转化为 测量E2-、E3-和E4-表达个体在休息时和认知过程中的基础代谢率， 挑战.使用O2和CO2记录，我们将计算呼吸交换率（RER），反映 碳水化合物/脂质氧化的比率，在每个试验中。根据APOE状态分析这些数据将 提供了对E2+个体底物利用的新认识，并提供了对潜在apoE的深入了解 对外周和神经能量反应的影响。如果成功，该提案将提供新的目标， 描述E2个体的神经保护代谢特征，并设计未来的治疗方法， 这些影响。通过使能量平衡发生“E2样”变化来增强大脑代谢， 预防或延缓AD的发生。

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.