DIFFERENTIAL EXPRESSION OF CHOLESTEROL HYDROXYLASES IN ALZHEIMER'S DISEASE

阿尔茨海默病中胆固醇羟化酶的差异表达

• 批准号: 7355279
• 负责人: JAMES BROWN
• 金额: $ 0.59万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7355279
• 关键词: DIFFERENTIAL; EXPRESSION; CHOLESTEROL; HYDROXYLASES; ALZHEIMER

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.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。胆固醇是通过氧化从神经元中清除出来的，这会产生氧固醇。胆固醇氧化是由胆固醇24-羟基酶(CYP46A1)和胆固醇27-羟基酶(CYP27A1)介导的。免疫细胞化学研究表明，正常脑内神经元和部分星形胶质细胞表达细胞色素P46A1和细胞色素P27A1，少突胶质细胞表达细胞色素P27A1。在阿尔茨海默病(AD)中，CYP46A1在星形胶质细胞和淀粉样斑块周围有显著表达，而在神经元中表达减少，在淀粉样斑块周围表达不明显，但在少突胶质细胞中表达增加。尽管以前的研究已经研究了合成氧固醇对淀粉样前体蛋白(APP)加工的影响，但自然产生的氧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，并分析了这两种胆固醇羟基酶在人脑中的细胞特异性表达模式。两种氧化甾醇都抑制神经元中A的产生，但24(S)-羟基胆固醇的效力是27-羟基胆固醇的1000倍。24-(S)-羟基胆固醇抑制A分泌的IC50为1 nM。两种氧化甾醇均可诱导ABCA1表达，其IC50值与抑制A分泌的IC50值相近，提示肝X受体参与了ABCA1的表达。氧化甾醇还抑制蛋白激酶C的活性和蛋白激酶C刺激后APP的分泌。神经炎斑块周围细胞色素P46A1的选择性表达和24(S)-羟基胆固醇对神经元APP加工的有效抑制表明细胞色素P46A1影响AD的病理生理学，并为研究CYP46A1基因的多态如何影响这一流行疾病的病理生理学提供了洞察力。