Investigating the impact of APOE on cerebral energetics

研究 APOE 对大脑能量学的影响

• 批准号: 10468319
• 负责人: Janice Jin Hwang
• 金额: --
• 依托单位: YALE UNIVERSITY
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468319
• 关键词: Adverse effects; Affect; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Anatomy; Animal Model; Animals; Apolipoprotein E; Attention; Blood - brain barrier anatomy; Body mass index; Brain; Brain scan; Cerebrovascular Disorders; Cerebrum; Closure by clamp; Cognitive; Data; Defect; Dementia; Development; Disease; Energy Metabolism; Epidemiology; Exposure to; Fatty Acids; Foundations; Framingham Heart Study; Functional disorder; Future; Genotype; Glucose; Goals; Homeostasis; Hour; Human; Hyperglycemia; Individual; Infusion procedures; Insulin Resistance; Kinetics; Lipids; MRI Scans; Magnetic Resonance Spectroscopy; Measures; Metabolic dysfunction; Mus; Neurocognitive; Neurodegenerative Disorders; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Palmitic Acids; Participant; Pathogenesis; Pathway interactions; Pattern; Plasma; Positron-Emission Tomography; Predisposition; Research Design; Risk; Risk Factors; Role; Saturated Fatty Acids; Scanning; Synapses; Testing; Thinness; Tissues; Translating; apolipoprotein E-4; carrier status; cohort; dementia risk; effective therapy; fatty acid metabolism; fluorodeoxyglucose; frontal lobe; genetic risk factor; glucose metabolism; glucose transport; imaging modality; insight; neuron loss; non-invasive imaging; novel; obese person; synaptic failure; uptake

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.

项目概要 尽管在了解阿尔茨海默病及其相关疾病的发病机制方面取得了巨大进展 痴呆症（ADRD），有效的治疗方法仍然难以捉摸，而且最有希望的治疗方法也未能成功 从动物模型转化为人类。虽然脑代谢低下长期以来一直是 AD 的一个标志，但 主要被认为是神经元损失和突触衰竭的结果。相对较少 人们注意到早期脑能量代谢变化的潜在影响 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型糖尿病都是阿尔茨海默病等神经退行性疾病发生的危险因素。 我们最近发现，肥胖和较高水平的非酯化脂肪酸 (NEFA) 与 大脑葡萄糖转运减弱。 APOE基因型是AD的主要危险因素之一。鉴于 APOE 在 外周和大脑中的脂质稳态以及多项研究表明 APOE4 携带者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。研究结果 这些研究将对 ADRD 产生重要影响。中心假设是认知正常， 携带至少一种 APOE4 等位基因的相对年轻的个体将会减少脑葡萄糖转运 使用 1H 磁共振波谱脑部扫描测量的容量与年龄和 BMI 的比较 匹配的对照受试者是 APOE3/3 纯合子，并且肥胖和肥胖会加剧这种情况 暴露于高循环脂肪酸。