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.