Alterations in phosphatidylethanolamine levels affect the generation of Aβ.
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.
Center for Human Genetics, Leuven Institute for Neurodegenerative diseases, KU Leuven, Leuven, Belgium.
Iva
I
Nesic
Francesc X
FX
Guix
Krist'l
K
Vennekens
Vasiliki
V
Michaki
Paul P
PP
Van Veldhoven
Fabian
F
Feiguin
Bart
B
De Strooper
Carlos G
CG
Dotti
Tina
T
Wahle
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D000818:Animals; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008297:Male; D021962:Membrane Microdomains / Q000737:chemistry / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010714:Phosphatidylethanolamines / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats
D016564:Amyloid beta-Protein Precursor; D003902:Detergents; D008565:Membrane Proteins; D010714:Phosphatidylethanolamines; D034741:RNA, Small Interfering; C483858:phosphatidylethanolamine; D002784:Cholesterol; D053829:Amyloid Precursor Protein Secretases