Investigating the impact of APOE on cerebral energetics

项目摘要 尽管在了解阿尔茨海默病的发病机制及其相关疾病方面取得了很大进展， 痴呆症（ADRD），有效的治疗仍然难以捉摸，最有希望的治疗方法未能 从动物模型转化到人类身上。虽然脑代谢低下长期以来一直是AD的标志，但它 主要被认为是神经元损失和突触失效的结果。相对较少 人们已经注意到脑能量代谢变化的潜在影响， 尽管有令人信服的流行病学证据表明肥胖、胰岛素抵抗和 2型糖尿病都是神经退行性疾病如阿尔茨海默病发展的危险因素。 我们最近的研究表明，肥胖和高水平的非酯化脂肪酸（NEFA）与 大脑葡萄糖转运受阻 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，以及几项研究表明APOE 4 携带者状态直接影响脂肪酸代谢，本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。这些发现 这些研究将对ADRD产生重要影响。核心假设是认知正常， 携带至少一个APOE 4等位基因的相对年轻的个体将具有降低的脑葡萄糖转运 与年龄和BMI相比，使用1H磁共振波谱脑扫描测量的能力 匹配的APOE 3/3纯合子对照受试者，肥胖会增强这一点， 接触高循环脂肪酸。

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.