The role of seladin-1/DHCR24 in cholesterol biosynthesis, APP processing and Aβ generation in vivo
The role of seladin-1/DHCR24 in cholesterol biosynthesis, APP processing and Aβ generation in vivo
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DOI：
10.1038/sj.emboj.7600938
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发表时间：
2006-01-25
期刊：
影响因子：
11.4
通讯作者：
Mohajeri, MH
中科院分区：
文献类型：
--
作者：
Crameri, A;Biondi, E;Mohajeri, MH
由Dhcr 24基因编码的胆固醇合成酶seladin-1是黄素腺嘌呤二核苷酸依赖性氧化还原酶，并调节对致癌和氧化刺激的反应。它具有神经保护作用，并在阿尔茨海默病（AD）中受影响的神经元中下调。在这里，我们发现seladin-1缺陷小鼠大脑胆固醇水平降低，富含胆固醇的抗洗涤剂膜结构域（DRM）紊乱。这与纤溶酶原结合和纤溶酶活化效率低下、β-分泌酶（BACE）从DRM置换为含APP的膜组分、APP β-裂解增加和A β肽水平高有关。相反，seladin-1的过表达增加了胆固醇和DRM组分向DRM组分中的募集，诱导了纤溶酶活化并减少了APP和A β形成的BACE加工。这些结果确立了seladin-1在DRM形成中的作用，并表明seladin-1依赖性胆固醇合成参与降低A β水平。seladin-1活性的药理学增强可能是治疗AD的新的A β降低方法。
The cholesterol-synthesizing enzyme seladin-1, encoded by the Dhcr24 gene, is a flavin adenine dinucleotide-dependent oxidoreductase and regulates responses to oncogenic and oxidative stimuli. It has a role in neuroprotection and is downregulated in affected neurons in Alzheimer's disease (AD). Here we show that seladin-1-deficient mouse brains had reduced levels of cholesterol and disorganized cholesterol-rich detergent-resistant membrane domains (DRMs). This was associated with inefficient plasminogen binding and plasmin activation, the displacement of beta-secretase ( BACE) from DRMs to APP-containing membrane fractions, increased beta-cleavage of APP and high levels of A beta peptides. In contrast, overexpression of seladin-1 increased both cholesterol and the recruitment of DRM components into DRM fractions, induced plasmin activation and reduced both BACE processing of APP and A beta formation. These results establish a role of seladin-1 in the formation of DRMs and suggest that seladin-1-dependent cholesterol synthesis is involved in lowering A beta levels. Pharmacological enhancement of seladin-1 activity may be a novel A beta-lowering approach for the treatment of AD.