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- Title
The role of seladin-1/DHCR24 in cholesterol biosynthesis, APP processing and Abeta generation in vivo.
- Authors
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
- Abstract
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.
- Publication
The EMBO journal, 2006, Vol 25, Issue 2, p432
- ISSN
0261-4189
- Publication type
Journal Article
- DOI
10.1038/sj.emboj.7600938