Investigating the impact of APOE on cerebral energetics

研究 APOE 对大脑能量学的影响

• 批准号: 10755052
• 负责人: Janice Jin Hwang
• 金额: $ 19.44万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10755052
• 关键词: Investigating; impact; APOE; cerebral; energetics

Project summary Despite great advances in understanding the pathogenesis of Alzheimer's disease and its related dementias (ADRD), effective treatments still remain elusive and most promising therapies have failed to translate from animal models into humans. While cerebral hypometabolism has long been a hallmark of AD, it has been predominantly considered a consequence of neuronal loss and synaptic failure. Relatively little attention has been paid to the potential impact of changes in cerebral energy metabolism early in the pathogenesis of disease despite compelling epidemiological evidence that obesity, insulin resistance, and type 2 diabetes are all risk factors for the development of neurodegenerative diseases such as Alzheimer's disease. We have recently shown that obesity and higher levels of non-esterified fatty acids (NEFA) are associated with blunted cerebral glucose transport. APOE genotype is one of the primary risk factors for AD. Given the important role that APOE has in lipid homeostasis in the periphery and the brain and the fact that several studies have shown that APOE4 carrier status directly affects fatty acid metabolism, the goals of this R21 are to determine whether and how APOE status can modulate the relationships between obesity, NEFA, and brain glucose transport. The findings from these studies will have important implications for ADRD. The central hypothesis is that cognitively normal, relatively young individuals who carry at least one APOE4 allele will have decreased cerebral glucose transport capacity measured using 1H magnetic resonance spectroscopy brain scanning compared to age and BMI matched control subjects who are homozygous APOE3/3 and that this will be potentiated by obesity and exposure to high circulating fatty acids.

项目摘要 尽管在了解阿尔茨海默氏病及其相关的发病机理方面取得了巨大进步 痴呆症（ADRD），有效治疗仍然难以捉摸，大多数有前途的疗法未能 从动物模型转化为人类。虽然脑失代谢长期以来一直是AD的标志 主要被认为是神经元丧失和突触衰竭的结果。相对较少 人们注意了早期脑能量代谢变化的潜在影响 疾病的发病机理尽管令人信服的流行病学证据表明肥胖，胰岛素抵抗和类型 2糖尿病都是神经退行性疾病（例如阿尔茨海默氏病）发展的危险因素。 我们最近表明，肥胖和较高水平的非酯化脂肪酸（NEFA）与 钝化的脑葡萄糖转运。 APOE基因型是AD的主要风险因素之一。考虑到Apoe在 外围和大脑中的脂质稳态以及一些研究表明APOE4的事实 载体状态直接影响脂肪酸代谢，该R21的目标是确定是否以及如何 APOE状态可以调节肥胖，NEFA和脑葡萄糖转运之间的关系。发现 从这些研究中将对ADRD具有重要意义。中心假设是认知正常， 携带至少一个APOE4等位基因的相对年轻的个体将减少脑葡萄糖转运 与年龄相比，使用1H磁共振光谱脑扫描测量的容量 纯合子APOE3/3的匹配对照对象，这将由肥胖和 暴露于高循环脂肪酸。