Cyp46 regulation of cholesterol efflux and ABeta

描述（由申请人提供）：先前的研究表明，降低胆固醇水平与降低阿尔茨海默病的风险相关。胆固醇外排在胆固醇稳态中起作用，可能是控制大脑胆固醇水平的重要目标。这项研究将为胆固醇外排和APP加工提供更好的理解。该研究将确定增加大脑特异性CYP46的表达是否会改变β水平。使用神经元和神经胶质培养，24s -羟基胆固醇将通过CYP46瞬时转染增加，将测量β水平。该研究将确定通过RNAi抑制CYP46是否会改变大脑的β水平。本研究还将探讨人类APOE基因型是否会在初代胶质细胞培养中对胆固醇外排产生不同的影响，以及高胆固醇水平是否会调节这些差异。这一基础科学可能有助于有效控制大脑中胆固醇水平的发展，并可能导致阿尔茨海默病患者未来的临床治疗。

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.