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...

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Bibliographic Details
Published in:PloS one 2010-02, Vol.5 (2), p.e9079
Main Authors: Yahi, Nouara, Aulas, Anaïs, Fantini, Jacques
Format: Article
Language:English
Subjects:
Alzheimer Disease - metabolism
Alzheimer's disease
Alzheimers disease
Amyloid beta-Peptides - chemistry
Amyloid beta-Peptides - metabolism
Antigens
Biochemistry
Biochemistry, Molecular Biology
Biophysics/Biomacromolecule-Ligand Interactions
Biophysics/Experimental Biophysical Methods
Cell surface
Ceramide
Cholesterol
Cholesterol - chemistry
Cholesterol - metabolism
Conformation
Crystallography
Crystallography, X-Ray
Dilution
Fatty acids
Fatty Acids - chemistry
Fatty Acids - metabolism
G(M1) Ganglioside - chemistry
G(M1) Ganglioside - metabolism
G(M3) Ganglioside - chemistry
G(M3) Ganglioside - metabolism
Glycolipids - chemistry
Glycolipids - metabolism
Glycosphingolipids
Glycosphingolipids - chemistry
Glycosphingolipids - metabolism
Helicobacter pylori
HIV
Human immunodeficiency virus
Humans
Life Sciences
Lipid Bilayers - chemistry
Lipid Bilayers - metabolism
Lipids
Lymphoma
Models, Molecular
Molecular Conformation
Molecular dynamics
Molecular Dynamics Simulation
Molecular modelling
Molecular Structure
Monolayers
Neurodegenerative diseases
Neurological Disorders/Alzheimer Disease
Oligomerization
Pathogenesis
Peptide Fragments - chemistry
Peptide Fragments - metabolism
Peptides
Protein Binding - drug effects
Proteins
Sodium Chloride - pharmacology
Sugar
Surface Properties
β-Amyloid
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0009079