Crameri Arames, Biondi Elisa, Kuehnle Katrin, Lütjohann Dieter, Thelen Karin M, Perga Simona, Dotti Carlos G, Nitsch Roger M, Ledesma Maria Dolores, Mohajeri M Hasan
Division of Psychiatry Research, University of Zurich, Zurich, Switzerland.
EMBO J. 2006 Jan 25;25(2):432-43. doi: 10.1038/sj.emboj.7600938. Epub 2006 Jan 12.
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 Abeta 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 Abeta 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 Abeta levels. Pharmacological enhancement of seladin-1 activity may be a novel Abeta-lowering approach for the treatment of AD.
由Dhcr24基因编码的胆固醇合成酶seladin-1是一种黄素腺嘌呤二核苷酸依赖性氧化还原酶，可调节对致癌和氧化刺激的反应。它在神经保护中发挥作用，在阿尔茨海默病（AD）的受影响神经元中表达下调。在此我们表明，seladin-1缺陷型小鼠大脑中的胆固醇水平降低，富含胆固醇的抗去污剂膜结构域（DRM）紊乱。这与纤溶酶原结合和纤溶酶激活效率低下、β-分泌酶（BACE）从DRM转移至含APP的膜组分、APP的β-切割增加以及高水平的Aβ肽有关。相反，seladin-1的过表达增加了胆固醇以及DRM组分向DRM组分的募集，诱导纤溶酶激活，并减少了APP的BACE加工和Aβ形成。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Aβ水平。seladin-1活性的药理学增强可能是一种治疗AD的新型降低Aβ水平的方法。
