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Title: Alterations in phosphatidylethanolamine levels affect the generation of Aβ
Authors: Nesic, Iva
Guix, Francesc
Vennekens, Kristel
Michaki, Vasiliki
Van Veldhoven, Paul P
Feiguin, Fabian
De Strooper, Bart
Dotti, Carlos
Wahle, Tina # ×
Issue Date: Feb-2012
Publisher: Blackwell Pub.
Series Title: Aging Cell vol:11 issue:1 pages:63-72
Article number: 10.1111/j.1474-9726.2011.00760.x
Abstract: Several studies suggest that the generation of Aβ is highly dependent on the levels of cholesterol within membranes' detergent-resistant microdomains (DRM). Indeed, the β-amyloid precursor protein (APP) cleaving machinery, namely β- and γ-secretases, has been shown to be present in DRM and its activity depends on membrane cholesterol levels. Counterintuitive to the localization of the cleavage machinery, the substrate, APP, localizes to membranes' detergent-soluble microdomains enriched in phospholipids (PL), indicating that Aβ generation is highly dependent on the capacity of enzyme and substrate to diffuse along the lateral plane of the membrane and therefore on the internal equilibrium of the different lipids of DRM and non-DRM domains. Here, we studied to which extent changes in the content of a main non-DRM lipid might affect the proteolytic processing of APP. As phosphatidylethanolamine (PE) accounts for the majority of PL, we focused on its impact on the regulation of APP proteolysis. In mammalian cells, siRNA-mediated knock-down of PE synthesis resulted in decreased Aβ owing to a dual effect: promoted α-secretase cleavage and decreased γ-secretase processing of APP. In vivo, in Drosophila melanogaster, genetic reduction in PL synthesis results in decreased γ-secretase-dependent cleavage of APP. These results suggest that modulation of the membrane-soluble domains could be a valuable alternative to reduce excessive Aβ generation.
URI: 
ISSN: 1474-9718
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory for the Research of Neurodegenerative Diseases
Laboratory of Neuronal Differentiation
Laboratory of Lipid Biochemistry and Protein Interactions
× corresponding author
# (joint) last author

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