β淀粉样蛋白调控星形胶质细胞胆固醇转运与代谢的机制及在阿尔茨海默病中的作用

The roles of cholesterol metabolism in the pathogenesis of Alzheimer’s disease(AD) have received increasing attention recently. Our previous study showed that β-amyloid(Aβ), crucially involved in AD, could stimulate GSH release from astrocytes likely by reducing astrocyte cholesterol level. However, the mechanism of Aβ reducing astrocyte cholesterol level remains unknown. Our preliminary results showed that Aβ increased the expression of ABCA1 and ABCG1. We hypothesize that Aβ could affect cholesterol metabolism and the functions of astrocytes through regulating cholesterol transport and/or synthesis. To test this hypothesis, we plan to use primary cultured astrocytes and 5×FAD transgenic mice, to study the effects of Aβ on ABCA1,ABCG1 and HMGCR expression and on cholesterol metabolism, by using techniques such as qPCR, immunofluorescence histochemistry , western blot, and pharmacologicaltools. The impact of cholesterol modulation on astrocytes will further be studied by HPLC and ion imaging.This study will provide new understandings on AD pathogenesis, and probably new therapeutic target for AD treatment.

胆固醇代谢在阿尔茨海默病（AD）发病中的作用与机制日趋受到重视。我们前期工作发现：AD的核心因素β淀粉样蛋白（β-amyloid，Aβ）可引起星胶胞内胆固醇的减少，由此促进星胶GSH的释放。然而Aβ引起星胶胆固醇减少的机制尚不清楚。我们的预实验结果提示Aβ可促进星胶胆固醇转运蛋白ABCA1和ABCG1的表达，为此我们提出假说：Aβ通过调控星胶胆固醇转运或合成的单一或多个环节引起胆固醇减少进而影响星胶功能。为验证这一假说，本课题拟采用原代培养的星胶和高表达Aβ的5×FAD小鼠模型，综合使用定量PCR，western-blot，免疫组化，结合对信号通路的药物学干预，研究Aβ对星胶胆固醇转运蛋白ABCA1，ABCG1和胆固醇合成酶HMGCR的表达调控及对胆固醇代谢的影响，进而以高效液相色谱与离子成像技术研究胆固醇水平对星胶细胞功能的影响。该课题有望为AD发病机制及治疗靶点的研究提供新的理论基础。