Biochemical Consequences of Regiospecific Metabolic Bias in the Brain

大脑区域特异性代谢偏差的生化后果

• 批准号: 10159813
• 负责人: John C. Price
• 金额: $ 59.03万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10159813
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Apolipoprotein E; Area; Biochemical; Biochemical Pathway; Brain; Brain region; Cardiovascular system; Clinical; Cognition; Contrast Media; Coupling; Data; Data Set; Development; Disease; Environmental Risk Factor; Enzymes; Exhibits; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Risk; Genotype; Hippocampus (Brain); Imaging Techniques; Individual; Inflammation; Investigation; Knowledge; Life Style; Lipids; Measures; Memory; Metabolic; Metabolic Control; Metabolic Pathway; Metabolism; Methods; Modeling; Monitor; Mus; Nerve Degeneration; Pathway interactions; Pattern; Persons; Positron-Emission Tomography; Protein Isoforms; Proteins; Proteomics; Regulation; Relative Risks; Resistance; Risk; Risk Factors; Stress; Surface; Synaptic plasticity; System; Techniques; Technology; Testing; Therapeutic; Tissues; Variant; age related; apolipoprotein E-3; apolipoprotein E-4; base; brain metabolism; desensitization; design; diet and exercise; genetic predictors; imaging modality; in vivo; insight; kinetic model; lipid metabolism; lipid transport; mass spectrometric imaging; mouse model; novel; physiologic stressor; prevent; repaired; risk variant

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.

发展心血管和阿尔茨海默氏神经变性（ND）的风险与以下因素密切相关： 载脂蛋白E（ApoE）多态性。有三种ApoE变体对ND风险具有不同的影响，其中 相对于变式3，变式2降低风险，变式4增加风险。这些ApoE变体也影响认知和记忆， 年轻健康个体，推测是通过ApoE的（初级）脂质转运功能。因此，一个主要假设是 脂质的运输在健康受试者中产生了代谢偏差，使这些受试者的大脑敏感（或保护）。 导致ND的生理压力。为了支持这一假设，生活方式的选择，包括运动和 饮食改变了代谢模式，改变了ND的风险，就像遗传易感性一样。基因的相互作用 和环境风险因素表明，预先存在的大脑代谢状况是一个关键的起始变量， 干预这种代谢偏差是预防疾病的可行方法。无法回答的问题， 然而，包括哪些代谢途径最受ApoE多态性的影响，以及年龄如何影响ApoE多态性。 加重代谢状况，促进ND。脂质代谢改变是长期炎症、细胞修复减少和能量可用性改变之间的统一变量，这些都促进了ND。我们已经开发了监测体内脂质和蛋白质周转的方法。将其与质谱（MS）成像相结合，我们可以看到整个大脑中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通量被同时测量，可能是监测代谢网络调节中ApoE依赖性变化的最敏感方法。很可能ApoE同种型使脂质递送偏向于脑的不同区域。这种偏差造成了新陈代谢的区域性长期变化，从而改变了因压力而造成损害的风险。比较ApoE2、ApoE3或E4小鼠模型之间的脑代谢变化以及每种基因型的年龄依赖性变化将有助于确定保护大脑免受损伤累积的代谢模式。 该提案的总体目标是监测代谢途径控制的区域变化，并确定ApoE 改变代谢流核心假设是ApoE2使代谢偏向于保护代谢的模式， 控制或调节，而ApoE4使脂质代谢偏向相反方向，导致年龄相关的更快的代谢。 代谢失控