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  • The EMBO Journal (2006) 25, 432 - 443
  • doi:10.1038/sj.emboj.7600938

Published online: 12 January 2006

The role of seladin-1/DHCR24 in cholesterol biosynthesis, APP processing and Abold beta generation in vivo

Arames Crameri1,a, Elisa Biondi2,a, Katrin Kuehnle1,a, Dieter Lütjohann3, Karin M Thelen3, Simona Perga2, Carlos G Dotti2,4, Roger M Nitsch1, Maria Dolores Ledesma2,4 and M Hasan Mohajeri1

  1. Division of Psychiatry Research, University of Zurich, Zurich, Switzerland
  2. Cavalieri Ottolenghi Scientific Institute, Università degli Studi di Torino, Orbassano, Italy
  3. Department of Clinical Pharmacology, University of Bonn, Germany
  4. Center for Human Genetics, Catholic University of Leuven and Flanders Interuniversitary Institute for Biotechnology (VIB4), Leuven, Belgium

Correspondence to:

Maria Dolores Ledesma, Cavalieri Ottolenghi Scientific Institute, Università degli Studi di Torino, AO San Luigi Gonzaga, Regione Gonzole 10, 10043 Orbassano, Turin, Italy. Tel.: +39 011 670 5482; Fax: +39 011 670 5449; E-mail: lola.ledesma@unito.it

M Hasan Mohajeri, Division of Psychiatry Research, University of Zurich, August-Forel Strasse 1, 8008 Zurich, Switzerland. Tel.: +41 44 634 8872; Fax: +41 44 634 8874; E-mail: mohajeri@bli.unizh.ch

aThese authors contributed equally to this work

Received 20 July 2005; Accepted 6 December 2005

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.

  • Keywords:

    • Abeta,
    • Alzheimer,
    • cholesterol,
    • neurodegeneration,
    • therapy