Cyp46 regulation of cholesterol efflux and ABeta

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DESCRIPTION (provided by applicant): Previous studies indicate that decreasing cholesterol levels correlates with a decreased risk of Alzheimer's disease. Cholesterol efflux plays a role in cholesterol homeostasis and may be an important target for controlling cholesterol levels in the brain. This study will provide a better understanding of cholesterol efflux and APP processing. The study will determine whether increasing expression of brain specific CYP46 will alter Abeta levels. Using neuronal and glial cultures, 24S-hydroxycholesterol will be increased thru CYP46 transient transfection Abeta levels will be measured. The study will determine whether CYP46 inhibition thru RNAi will alter brain Abeta levels. This study will also investigate whether the human APOE genotypes affect cholesterol efflux differently in primary glial cultures and whether high cholesterol levels modulate these differences. This basic science may assist in the development of effective controls for cholesterol levels in the brain and possibly lead to future clinical treatments in Alzheimer patients.