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。胆固醇流出在胆固醇稳态中起作用，并且可能是控制脑中胆固醇水平的重要靶点。这项研究将提供一个更好的了解胆固醇流出和APP加工。该研究将确定脑特异性CYP 46表达的增加是否会改变Abeta水平。使用神经元和神经胶质培养物，通过CYP 46瞬时转染将增加24 S-羟基胆固醇，并将测量Abeta水平。该研究将确定通过RNAi抑制CYP 46是否会改变脑Abeta水平。本研究还将调查人类APOE基因型是否影响胆固醇流出不同的原代胶质细胞培养，以及是否高胆固醇水平调节这些差异。这一基础科学可能有助于开发有效控制大脑胆固醇水平的方法，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.