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

代谢功能障碍，如肥胖的情况，有助于几个与年龄相关的疾病的发展 疾病，包括阿尔茨海默病(AD)。载脂蛋白E(ApoE)是血液循环的重要组成部分 在外周和大脑中都发现了脂蛋白，APOE基因编码了三种主要的亚型 人口：E2、E3和E4。E4是散发性AD最显著的遗传危险因素，而E2是 防护性的。与肥胖一样，E4亚型也与AD风险增加有关。矛盾的是，老鼠 携带E4基因的人患AD的风险增加，尽管肥胖程度降低，而携带E2基因的人患AD的风险更高 尽管肥胖增加，但仍能保护自己免受AD的侵害。我们在老鼠身上的初步发现表明，这两个因素 -肥胖和载脂蛋白E-可能通过与能量底物偏好有关的统一生物机制联系在一起， 对AD的预防和个体化(遗传)治疗具有广泛的意义。我们的中央 假设apoE的亚型不同地改变了兰德尔循环的平衡：E2有利于葡萄糖，E4有利于 对FA的青睐。具体地说，我们假设E2通过代谢发挥其神经保护作用。 偏爱葡萄糖的利用，而不是脂肪酸氧化。为了检验E2提供的假说 通过减少脂肪酸氧化和增加葡萄糖利用率来保护神经，我们将定量跟踪 通过稳定同位素提供的独特前体产物“追踪”进入底物和新陈代谢 分解代谢组学(SIRM)。然后，我们将使用多组学方法将SIRM结果与 表达人载脂蛋白E的小鼠和细胞的转录图谱分析 在大脑和外周，E2的表达改变了信号通路。最后，我们将通过以下方式来翻译我们的发现 在静息和认知过程中测量表达E2、E3和E4的个体的基础代谢率 挑战。使用O2和CO2记录，我们将计算呼吸交换率(RER)，这反映了 每项试验中碳水化合物/脂肪氧化的比率。根据APOE状态分析这些数据将 提供了对E2+个体底物利用的新理解，并提供了对潜在载脂蛋白E的洞察 对外周和神经能量反应的影响。如果成功，这项提议将提供新的目标，通过 表征E2个体的神经保护性代谢特征，并设计未来的治疗方法以模拟 这些影响。通过对能量平衡进行类似于E2的改变来增强大脑新陈代谢可能有很大的好处 在预防或延缓阿尔茨海默病发病方面的作用。

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.