Biochemical Consequences of Regiospecific Metabolic Bias in the Brain

发生以心血管为基础的和阿尔茨海默氏神经变性(ND)的风险与 载脂蛋白E(ApoE)基因多态性。有三种载脂蛋白E变体对新城疫风险有不同的影响，其中 与变体3相比，变体2降低了风险，而4则增加了风险。这些ApoE变体也会影响认知和记忆 年轻健康的个体，可能通过载脂蛋白E(主要)的脂质运输功能。因此，一个重要的假设是 脂类的运输在健康受试者中造成代谢偏差，从而使这些人的大脑敏感(或保护) 受到生理压力，导致新城疫。为了支持这一假设，生活方式的选择包括锻炼和 饮食改变了新陈代谢模式，改变了新城疫的风险，也改变了遗传易感性。基因的相互作用 环境风险因素表明，大脑先前存在的新陈代谢状况是一个关键的启动变量， 对这种代谢偏差进行干预是预防疾病的一种可行方法。悬而未决的问题， 然而，包括哪些代谢途径受ApoE多态影响最大，以及年龄是如何变化的 夸大新陈代谢状态，促进新陈代谢。脂质代谢的改变是长期炎症、细胞修复减少和能量供应改变之间的统一变量，这些因素都促进了ND。我们已经开发了监测体内脂类和蛋白质周转的方法。结合质谱学(MS)成像，我们可以看到整个大脑在空间上不同的体内代谢调节。系统水平的研究，其中许多脂质和蛋白质的流量被同时测量，可能是监测代谢网络调节中依赖于载脂蛋白E的变化的最敏感的方法。可能是载脂蛋白E亚型偏向将脂质输送到大脑的不同区域。这种偏见造成了新陈代谢的区域性长期变化，从而改变了因压力造成损害的风险。比较APOE2、ApoE3或E4小鼠模型中脑代谢的变化，以及每种基因型的年龄相关性变化，将有助于识别保护大脑免受损伤积累的代谢模式。 这项提案的总体目标是监测代谢途径控制的区域性变化，并确定载脂蛋白E是如何 改变新陈代谢流量。中心假说是APOE2偏向保护新陈代谢的模式 控制或调节，而载脂蛋白E4以相反的方向偏向脂类代谢，导致更快的年龄相关 失去新陈代谢控制。

Risks for developing cardiovascular‐based and Alzheimer’s neurodegeneration (ND) are strongly connected to Apolipoprotein E (ApoE) polymorphisms. There are three ApoE variants with differential impacts on ND risk, where variant 2 reduces and 4 increases risk relative to variant 3. These ApoE variants also impact cognition and memory in young healthy individuals, presumably through ApoE’s (primary) lipid transport function. Thus, a leading hypothesis is that the transport of lipids creates a metabolic bias in healthy subjects that sensitizes (or protects) the brains of these subjects to physiological stresses which leads to ND. In support of this hypothesis, lifestyle choices including exercise and diet, which shift metabolic patterns, modify the risk of ND as much as genetic predisposition. The interplay of genetic and environmental risk factors indicate that the preexisting metabolic condition of the brain is a key initiating variable, and that interceding in this metabolic bias represents a viable method for preventing disease. Unanswered questions, however, include which metabolic pathways are most impacted by the ApoE polymorphism, and how does age exaggerate the metabolic condition to promote ND. Modified lipid metabolism is a unifying variable between long‐term inflammation, reduced cellular repair and modified energy availability which all promote ND. We have developed methods to monitor the turnover of lipids and proteins in vivo. Coupling this with mass spectrometric (MS) imaging, we can see spatially distinct in vivo metabolic regulation across the brain. A systems‐level investigation, in which the fluxes of many lipids and proteins are simultaneously measured, may be the most sensitive approach to monitor ApoE‐dependent changes in regulation of metabolic networks. It is probable that the ApoE isoforms bias lipid delivery to different regions of the brain. This bias creates regional long‐term shifts in metabolism, which change the risk for damage due to stress. Comparison of changes in brain metabolism between ApoE2, ApoE3, or E4 mouse models and the age‐dependent changes for each genotype will help to identify metabolic patterns that protect the brain from accumulation of damage. The overall objective of this proposal is to monitor regional changes in metabolic pathway control and identify how ApoE shifts metabolic flux. The central hypothesis is that ApoE2 biases metabolism to a pattern that protects metabolic control or regulation, while ApoE4 biases lipid metabolism in the opposite direction resulting in more rapid age‐related loss of metabolic control.