Investigating the impact of APOE on cerebral energetics

项目总结 尽管对阿尔茨海默病及其相关疾病的发病机制的了解取得了很大进展 痴呆症(ADRD)，有效的治疗方法仍然难以捉摸，大多数有希望的治疗方法都未能奏效 从动物模型移植到人类身上。虽然大脑代谢不足长期以来一直是阿尔茨海默病的一个标志，但它 主要被认为是神经元丢失和突触衰竭的结果。相对较少 在早期，人们已经注意到大脑能量代谢变化的潜在影响。 疾病的发病机制，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糖尿病都是阿尔茨海默病等神经退行性疾病发展的危险因素。 我们最近发现，肥胖和较高水平的非酯化脂肪酸(NEFA)与 大脑葡萄糖转运迟钝。 APOE基因是AD的主要危险因素之一。鉴于APOE在 外周和大脑中的脂质动态平衡以及几项研究表明载脂蛋白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 载脂蛋白E状态可以调节肥胖、NEFA和脑葡萄糖转运之间的关系。调查结果 这些研究将对ADRD产生重要影响。中心假设是认知正常， 携带至少一个APOE4等位基因的相对年轻的个体将会降低大脑葡萄糖转运 1H磁共振脑扫描测量容量与年龄和BMI的比较 匹配的对照组受试者是APOE3/3纯合子，肥胖和 暴露在高循环脂肪酸中。

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.