Cyp46 regulation of cholesterol efflux and ABeta

描述(由申请人提供)：以前的研究表明，降低胆固醇水平与降低阿尔茨海默病的风险相关。胆固醇外流在胆固醇动态平衡中起着重要作用，可能是控制脑内胆固醇水平的重要靶点。这项研究将对胆固醇外流和APP的处理提供更好的理解。这项研究将确定大脑特异性细胞色素P46的表达增加是否会改变Abeta水平。利用神经元和神经胶质细胞培养，24S-羟基胆固醇将通过CYP46瞬时转染法增加，Abeta水平将被测量。这项研究将确定通过RNAi抑制CYP46是否会改变大脑Abeta的水平。这项研究还将调查在原代胶质细胞培养中，人类载脂蛋白E基因型别是否影响胆固醇流出的不同，以及高胆固醇水平是否调节这些差异。这项基础科学可能有助于开发对大脑中胆固醇水平的有效控制，并可能导致未来对阿尔茨海默病患者的临床治疗。

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.