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

项目总结/摘要：星形胶质细胞中的脂肪酸运输：线粒体的作用 形态学和脂滴动力学 随着美国人口老龄化，痴呆症和肥胖相关的负担 疾病正在增加。越来越多的证据表明，肥胖、代谢综合征和糖尿病可以 导致老年痴呆症的发展因此，关键是 了解新陈代谢和神经退化之间的相互作用。一种候选蛋白质连接 AD是ApoE。ApoE参与脂质的转运，包括脂肪酸（FA）和 胆固醇，在大脑中。在所有已确定的发生迟发性AD的遗传风险因素中， APOE基因的一种称为APOE 4等位基因的变体是最强的风险预测因子。ApoE 4蛋白如何 导致AD进展的原因尚不清楚。ApoE通常不在神经元中表达，但在神经元中表达。 在星形胶质细胞中表达。星形胶质细胞是大脑中的细胞，为神经元提供许多代谢产物， 块，包括FA。拟议的研究将使用先进的显微镜技术来调查 星形胶质细胞内以及星形胶质细胞和神经元之间的FA储存、代谢和运输。在Aim中 1，将检查ApoE对星形胶质细胞中FA储存和代谢的影响。ApoE的作用 还将测试星形胶质细胞中的表达对FA从星形胶质细胞转移到神经元的影响， 将确定FA从星形胶质细胞转移到神经元对神经元健康和突触发生的影响。在Aim中 2、对ApoE影响线粒体形态和功能的假说进行验证。线粒体是 负责代谢脂肪酸的细胞区室。ApoE与线粒体 功能障碍，但机制尚不清楚。最后，在目标3中，ApoE影响相互作用的假设 将研究脂滴和其他细胞区室之间的关系。脂滴是细胞 负责储存脂肪的隔室。因此，脂滴和其他细胞之间的脂肪酸交换， 负责合成和氧化FA的隔室可能会对FA运输产生影响 在星形胶质细胞内，以及在星形胶质细胞和神经元之间。总之，这些研究将提供深入了解 新陈代谢和神经退化之间的联系这可能导致早期干预的新方法 减缓或预防阿尔茨海默病，例如通过靶向控制阿尔茨海默病的代谢途径， 在星形胶质细胞中储存或运输FA。这种干预措施有可能大大改善 阿尔茨海默病和其他痴呆症患者的生活质量。

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.