Fatty acid trafficking in astrocytes: role of mitochondrial morphology and lipid droplet dynamics

星形胶质细胞中的脂肪酸运输：线粒体形态和脂滴动力学的作用

• 批准号: 9658631
• 负责人: Sarah Cohen
• 金额: $ 24.9万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-15 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9658631
• 关键词: Affect; Age; Alleles; Alzheimer' s Disease; Apolipoprotein E; Astrocytes; Award; Biochemical; Biological Assay; Brain; Cells; Cholesterol; Dementia; Dependence; Diabetes Mellitus; Disease; Early Intervention; Early Onset Familial Alzheimer' s Disease; Endoplasmic Reticulum; Fatty Acids; Fatty acid glycerol esters; Genes; Health; Human; Image; Image Analysis; Impairment; Intervention; Knockout Mice; Late Onset Alzheimer Disease; Lead; Link; Lipids; Lipoproteins; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolic syndrome; Metabolism; Microscopy; Mission; Mitochondria; Morphology; Nerve Degeneration; Neurons; Obesity; Organelles; Oxides; Patient-Focused Outcomes; Patients; Phase; Play; Population; Primary Cell Cultures; Proteins; Quality of life; Research; Risk; Risk Factors; Role; Small Interfering RNA; Techniques; Testing; Training; Triglycerides; United States; Work; apolipoprotein E-3; apolipoprotein E-4; career; computer program; diabetes risk; disability; exosome; genetic risk factor; improved; improved outcome; insight; link protein; lipid transport; microvesicles; mitochondrial dysfunction; novel; novel strategies; oxidation; particle; prevent; synaptogenesis; trafficking

PROJECT SUMMARY/ABSTRACT: Fatty acid trafficking in astrocytes: role of mitochondrial morphology and lipid droplet dynamics As the population of the United States ages, the burden of both dementia and obesity-related disorders is increasing. There is mounting evidence that obesity, metabolic syndrome, and diabetes can contribute to the progression of dementias such as Alzheimer's disease. Therefore, it is crucial to understand the interplay between metabolism and neurodegeneration. A candidate protein linking metabolism and AD is ApoE. ApoE is involved in the transport of lipids, including fatty acids (FAs) and cholesterol, in the brain. Of all the identified genetic risk factors for developing late onset AD, a particular version of the APOE gene called the APOE4 allele is the strongest predictor of risk. How the ApoE4 protein contributes to the progression of AD is not understood. ApoE is not normally expressed in neurons, but is expressed in astrocytes. Astrocytes are cells in the brain that supply neurons with many metabolic building blocks, including FAs. The proposed study will use advanced microscopy techniques to investigate the storage, metabolism, and trafficking of FAs within astrocytes, and between astrocytes and neurons. In Aim 1, the effect of ApoE on FA storage and metabolism in astrocytes will be examined. The effect of ApoE expression in astrocytes on the transfer of FAs from astrocytes to neurons will also be tested, and the effect of FA transfer from astrocytes to neurons on neuronal health and synaptogenesis will be determined. In Aim 2, the hypothesis that ApoE affects mitochondrial morphology and function will be tested. Mitochondria are the cellular compartment responsible for metabolizing FAs. ApoE has been implicated in mitochondrial dysfunction, but the mechanism is unclear. Lastly, in Aim 3 the hypothesis that ApoE affects the interaction between lipid droplets and other cellular compartments will be investigated. Lipid droplets are the cellular compartment responsible for storing fat. Thus, the exchange of FAs between lipid droplets and other cellular compartments responsible for synthesizing and oxidizing FAs is likely to have an impact on FA trafficking within astrocytes, and between astrocytes and neurons. Together, these studies will provide insight into the links between metabolism and neurodegeneration. This could lead to new approaches for early intervention to slow or prevent Alzheimer's disease, for example by targeting metabolic pathways that control the storage or trafficking of FAs in astrocytes. Such interventions have the potential to dramatically improve the quality of life of patients suffering from Alzheimer's disease and other dementias.

项目摘要/摘要：星形胶质细胞中的脂肪酸运输：线粒体的作用 形态和脂质液滴动力学 作为美国年龄的人口，痴呆和肥胖有关的负担 疾病正在增加。有越来越多的证据表明肥胖，代谢综合征和糖尿病可以 有助于痴呆症的进展，例如阿尔茨海默氏病。因此，这对 了解代谢和神经退行性之间的相互作用。候选蛋白连接 代谢和广告是Apoe。 APOE参与脂质的运输，包括脂肪酸（FAS）和 胆固醇，大脑。在所有确定的遗传危险因素开发后期AD中，特定的 APOE基因的版本称为APOE4等位基因是风险的最强预测指标。 APOE4蛋白如何 尚不理解有助于AD的发展。 APOE通常在神经元中表达，而是 在星形胶质细胞中表达。星形胶质细胞是大脑中的细胞，可为神经元提供许多代谢建筑 块，包括FAS。拟议的研究将使用高级显微镜技术研究 在星形胶质细胞内以及星形胶质细胞和神经元之间的FAS的存储，代谢和贩运。目标 1，将检查APOE对星形胶质细胞中FA存储和代谢的影响。 apoe的效果 也将测试星形胶质细胞中FAS从星形胶质细胞转移到神经元的表达，并将测试效果 将确定从星形胶质细胞转移到神经元健康和突触发生的神经元的转移。目标 2，将测试APOE影响线粒体形态和功能的假设。线粒体是 负责代谢FA的细胞室。 APOE与线粒体有关 功能障碍，但机制尚不清楚。最后，在AIM 3中，APOE影响相互作用的假设 将研究脂质液滴和其他细胞室之间。脂质液滴是细胞 负责储存脂肪的车厢。因此，脂质液滴和其他细胞之间的FAS交换 负责合成和氧化FA的车间可能会对FA贩运产生影响 在星形胶质细胞内以及星形胶质细胞和神经元之间。这些研究将共同​​洞悉 新陈代谢与神经退行性之间的联系。这可能会导致提早干预的新方法 减慢或预防阿尔茨海默氏病，例如，针对控制该疾病的代谢途径 FAS在星形胶质细胞中的存储或贩运。这种干预措施有可能显着改善 患有阿尔茨海默氏病和其他痴呆症患者的生活质量。