How cholesterol constrains glycolipid conformation for optimal recognition of Alzheimer's beta amyloid peptide (Abeta1-40).
Membrane lipids play a pivotal role in the pathogenesis of Alzheimer's disease, which is associated with conformational changes, oligomerization and/or aggregation of Alzheimer's beta-amyloid (Abeta) peptides. Yet conflicting data have been reported on the respective effect of cholesterol and glycosphingolipids (GSLs) on the supramolecular assembly of Abeta peptides. The aim of the present study was to unravel the molecular mechanisms by which cholesterol modulates the interaction between Abeta(1-40) and chemically defined GSLs (GalCer, LacCer, GM1, GM3). Using the Langmuir monolayer technique, we show that Abeta(1-40) selectively binds to GSLs containing a 2-OH group in the acyl chain of the ceramide backbone (HFA-GSLs). In contrast, Abeta(1-40) did not interact with GSLs containing a nonhydroxylated fatty acid (NFA-GSLs). Cholesterol inhibited the interaction of Abeta(1-40) with HFA-GSLs, through dilution of the GSL in the monolayer, but rendered the initially inactive NFA-GSLs competent for Abeta(1-40) binding. Both crystallographic data and molecular dynamics simulations suggested that the active conformation of HFA-GSL involves a H-bond network that restricts the orientation of the sugar group of GSLs in a parallel orientation with respect to the membrane. This particular conformation is stabilized by the 2-OH group of the GSL. Correspondingly, the interaction of Abeta(1-40) with HFA-GSLs is strongly inhibited by NaF, an efficient competitor of H-bond formation. For NFA-GSLs, this is the OH group of cholesterol that constrains the glycolipid to adopt the active L-shape conformation compatible with sugar-aromatic CH-pi stacking interactions involving residue Y10 of Abeta(1-40). We conclude that cholesterol can either inhibit or facilitate membrane-Abeta interactions through fine tuning of glycosphingolipid conformation. These data shed some light on the complex molecular interplay between cell surface GSLs, cholesterol and Abeta peptides, and on the influence of this molecular ballet on Abeta-membrane interactions.
Université Paul Cézanne (Aix-Marseille 3), Université de la Méditerranée (Aix-Marseille 2), Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, CNRS UMR 6231, INRA USC 2027, Interactions Moléculaires et Systèmes Membranaires, Faculté des Sciences Saint-Jérôme, Marseille, France.
Nouara
N
Yahi
Anaïs
A
Aulas
Jacques
J
Fantini
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism; D005677:G(M1) Ganglioside / Q000737:chemistry / Q000378:metabolism; D005679:G(M3) Ganglioside / Q000737:chemistry / Q000378:metabolism; D006017:Glycolipids / Q000737:chemistry* / Q000378:metabolism; D006028:Glycosphingolipids / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D012965:Sodium Chloride / Q000494:pharmacology; D013499:Surface Properties
D016229:Amyloid beta-Peptides; D005227:Fatty Acids; D005679:G(M3) Ganglioside; D006017:Glycolipids; D006028:Glycosphingolipids; D008051:Lipid Bilayers; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D005677:G(M1) Ganglioside; D012965:Sodium Chloride; D002784:Cholesterol