Clathrin-dependent APP endocytosis and Abeta secretion are highly sensitive to the level of plasma membrane cholesterol

Cossec, Jack-Christophe, Simon, Anne, Marquer, Catherine, Moldrich, Randal X., Leterrier, Christophe, Rossier, Jean, Duykaerts, Charles, Lenkei, Zsolt and Potier, Marie-Claude (2010) Clathrin-dependent APP endocytosis and Abeta secretion are highly sensitive to the level of plasma membrane cholesterol. BBA - Molecular and Cell Biology of Lipids, 1801 8: 846-852. doi:10.1016/j.bbalip.2010.05.010


Author Cossec, Jack-Christophe
Simon, Anne
Marquer, Catherine
Moldrich, Randal X.
Leterrier, Christophe
Rossier, Jean
Duykaerts, Charles
Lenkei, Zsolt
Potier, Marie-Claude
Title Clathrin-dependent APP endocytosis and Abeta secretion are highly sensitive to the level of plasma membrane cholesterol
Formatted title
Clathrin-dependent APP endocytosis and Aβ secretion are highly sensitive to the level of plasma membrane cholesterol
Journal name BBA - Molecular and Cell Biology of Lipids   Check publisher's open access policy
ISSN 1388-1981
Publication date 2010-08
Sub-type Article (original research)
DOI 10.1016/j.bbalip.2010.05.010
Volume 1801
Issue 8
Start page 846
End page 852
Total pages 7
Place of publication Amsterdam, Netherlands
Publisher Elsevier BV
Collection year 2011
Language eng
Abstract Several lines of evidence support a strong relationship between cholesterol and Alzheimer's disease pathogenesis. Membrane cholesterol is known to modulate amyloid precursor protein (APP) endocytosis and amyloid-β (Aβ) secretion. Here we show in a human cell line model of endocytosis (HEK293 cells) that cholesterol exerts these effects in a dose-dependent and linear manner, over a wide range of concentrations (-40% to + 40% variations of plasma membrane cholesterol induced by methyl-beta-cyclodextrin (MBCD) and MBCD-cholesterol complex respectively). We found that the gradual effect of cholesterol is inhibited by small interference RNA-mediated downregulation of clathrin. Modulation of clathrin-mediated APP endocytosis by cholesterol was further demonstrated using mutants of proteins involved in the formation of early endosomes (dynamin2, Eps15 and Rab5). Importantly we show that membrane proteins other than APP are not affected by cholesterol to the same extent. Indeed clathrin-dependent endocytosis of transferrin and cannabinoid1 receptors as well as internalization of surface proteins labelled with a biotin derivative (sulfo-NHS-SS-biotin) were not sensitive to variations of plasma membrane cholesterol from -40% to 40%. In conclusion clathrin-dependent APP endocytosis appears to be very sensitive to the levels of membrane cholesterol. These results suggest that cholesterol increase in AD could be responsible for the enhanced internalization of clathrin-, dynamin2-, Eps15- and Rab5-dependent endocytosis of APP and the ensuing overproduction of Aβ. Copyright © 2010 Elsevier B.V. All rights reserved.
Keyword Alzheimer's disease
Cholesterol
Endocytosis
Clathrin
Amyloidβ
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
Queensland Brain Institute Publications
 
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Created: Wed, 23 Feb 2011, 11:53:40 EST by Debra McMurtrie on behalf of Queensland Brain Institute