The role of seladin-1/DHCR24 in cholesterol biosynthesis, APP processing and Abeta generation in vivo.
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.
Crameri
Arames
A
Division of Psychiatry Research, University of Zurich, Zurich, Switzerland.
Biondi
Elisa
E
Kuehnle
Katrin
K
Lütjohann
Dieter
D
Thelen
Karin M
KM
Perga
Simona
S
Dotti
Carlos G
CG
Nitsch
Roger M
RM
Ledesma
Maria Dolores
MD
Mohajeri
M Hasan
MH
D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis* / Q000378:metabolism; D017931:DNA Primers; D010450:Endopeptidases / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D010958:Plasminogen / Q000378:metabolism; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric
C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D017931:DNA Primers; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D010958:Plasminogen; D002784:Cholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499055:DHCR24 protein, human; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D005341:Fibrinolysin; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse