Imaging cholesterol metabolic flux and transport underlying brain function

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Cholesterol in the central nervous system is separated from the rest of the body by the blood brain barrier. Disturbances in the synthesis, transport or metabolism of cholesterol in the central nervous system are associated with severe neurological and cognitive defects. Although the level of cholesterol in adult brain is at a steady-state there is a continuous turnover with an exquisite balance between de novo synthesis and metabolism. Brain cells synthesise cholesterol throughout life. Mounting evidence suggest that not only is the steady-state concentration of cholesterol important, but that cholesterol precursors and metabolites are also critical for effective brain activity, including learning, memory and motor function. Therefore, a continuous flow of metabolites through the cholesterol synthesis and metabolic pathways is essential to maintain brain function and measuring the spatial flux of metabolites in these pathways will provide further insight into the involvement of cholesterol in proper brain function. How the turnover of cholesterol differs in distinct brain regions and varies with age also affecting brain function is unclear. Furthermore, it is not known if local de novo cholesterol biosynthesis and generation of cholesterol-related molecules is essential for adult neurogenesis, as is the case in the embryo. In this project we will develop "next generation" mass spectrometry imaging technologies to answer these quandaries. Results from this study will be particularly important with the growing use of the statin class of drugs as inhibitors of cholesterol biosynthesis.