DIFFERENTIAL EXPRESSION OF CHOLESTEROL HYDROXYLASES IN ALZHEIMER'S DISEASE

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。胆固醇通过氧化作用从神经元中消除，从而产生氧固醇。胆固醇氧化由胆固醇24-羟化酶（CYP 46 A1）和胆固醇27-羟化酶（CYP 27 A1）介导。免疫细胞化学研究表明，CYP 46 A1和CYP 27 A1在正常脑中的神经元和一些星形胶质细胞中表达，而CYP 27 A1存在于少突胶质细胞中。在阿尔茨海默病（AD）中，CYP 46 A1在星形胶质细胞和淀粉样斑块周围显示出显著的表达，而CYP 27 A1表达在神经元中降低，在淀粉样斑块周围不明显，但在少突胶质细胞中增加。虽然以前的研究已经检查了合成的氧化固醇对淀粉样前体蛋白（APP）加工的影响，但天然存在的氧化固醇的作用还有待研究。为了了解胆固醇氧化在AD中的作用，我们比较了24（S）-和27-羟基胆固醇对APP加工的影响，并分析了人脑中两种胆固醇羟化酶的细胞特异性表达模式。这两种氧化固醇都能抑制神经元中A的产生，但24（S）-羟基胆固醇的作用比27-羟基胆固醇强1000倍。24（S）-羟基胆固醇抑制A分泌的IC 50为1 nM。两种氧化固醇均诱导ABCA 1表达，其IC 50值与抑制A分泌的IC 50值相似，表明肝脏X受体参与。氧化固醇还抑制蛋白激酶C活性和刺激蛋白激酶C后的APP分泌。CYP 46 A1在神经炎斑块周围的选择性表达和24（S）-羟基胆固醇对神经元中APP加工的强效抑制表明CYP 46 A1影响AD的病理生理学，并提供了CYP 46 A1基因多态性如何影响这种流行疾病的病理生理学的见解。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cholesterol is eliminated from neurons by oxidization, which generates oxysterols. Cholesterol oxidation is mediated by the enzymes cholesterol 24-hydroxylase (CYP46A1) and cholesterol 27-hydroxylase (CYP27A1). Immunocytochemical studies show that CYP46A1 and CYP27A1 are expressed in neurons and some astrocytes in the normal brain, and CYP27A1 is present in oligodendrocytes. In Alzheimer's disease (AD), CYP46A1 shows prominent expression in astrocytes and around amyloid plaques, whereas CYP27A1 expression decreases in neurons and is not apparent around amyloid plaques but increases in oligodendrocytes. Although previous studies have examined the effects of synthetic oxysterols on the processing of amyloid precursor protein (APP), the actions of the naturally occurring oxysterols have yet to be examined. To understand the role of cholesterol oxidation in AD, we compared the effects of 24(S)- and 27-hydroxycholesterol on the processing of APP and analyzed the cell-specific expression patterns of the two cholesterol hydroxylases in the human brain. Both oxysterols inhibited production of A in neurons, but 24(S)-hydroxycholesterol was 1000-fold more potent than 27-hydroxycholesterol. The IC50 of 24(S)-hydroxycholesterol for inhibiting A secretion was 1 nM. Both oxysterols induced ABCA1 expression with IC50 values similar to that for inhibition of A secretion, suggesting the involvement of liver X receptor. Oxysterols also inhibited protein kinase C activity and APP secretion following stimulation of protein kinase C. The selective expression of CYP46A1 around neuritic plaques and the potent inhibition of APP processing in neurons by 24(S)-hydroxycholesterol suggests that CYP46A1 affects the pathophysiology of AD and provides insight into how polymorphisms in the CYP46A1 gene might influence the pathophysiology of this prevalent disease.