How Cholesterol Constrains Glycolipid Conformation for Optimal Recognition of Alzheimer's β Amyloid Peptide (Aβ1-40)

Abstract

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 β-amyloid (Aβ) peptides. Yet conflicting data have been reported on the respective effect of cholesterol and glycosphingolipids (GSLs) on the supramolecular assembly of Aβ peptides. The aim of the present study was to unravel the molecular mechanisms by which cholesterol modulates the interaction between Aβ1–40 and chemically defined GSLs (GalCer, LacCer, GM1, GM3). Using the Langmuir monolayer technique, we show that Aβ1–40 selectively binds to GSLs containing a 2-OH group in the acyl chain of the ceramide backbone (HFA-GSLs). In contrast, Aβ1–40 did not interact with GSLs containing a nonhydroxylated fatty acid (NFA-GSLs). Cholesterol inhibited the interaction of Aβ1–40 with HFA-GSLs, through dilution of the GSL in the monolayer, but rendered the initially inactive NFA-GSLs competent for Aβ1–40 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 Aβ1–40 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-π stacking interactions involving residue Y10 of Aβ1–40. We conclude that cholesterol can either inhibit or facilitate membrane-Aβ interactions through fine tuning of glycosphingolipid conformation. These data shed some light on the complex molecular interplay between cell surface GSLs, cholesterol and Aβ peptides, and on the influence of this molecular ballet on Aβ-membrane interactions.

A Major Fraction of Glycosphingolipids in Model and Cellular Cholesterol-containing Membranes Is Undetectable by Their Binding Proteins

“…Molecular modeling the cholesterol-sphingolipid complex shows the polar cholesterol hydroxyl group (63), can form an H-bond network to alter the sugar conformation around the anomeric linkage, to be parallel, rather than perpendicular, to the membrane (61). We have found similar simulation results for GM1 ganglioside.…”

“…Membrane curvature may alter the plane of the membrane bilayer relative to the GSL carbohydrate (29,61) to affect ligand binding. GSL carbohydrate conformation may also affect membrane curvature and vesicle size.…”

Adamantyl Glycosphingolipids Provide a New Approach to the Selective Regulation of Cellular Glycosphingolipid Metabolism

“…GSLs can modulate membrane receptor function (3,4), are altered in cancer (5,6) and cell growth (7), and provide a primary target for host cell interaction with microbial pathogens (8). In addition, GSL accumulation has been identified to contribute to the pathology of many other diseases, including Parkinson disease (9,10), Alzheimer's disease (11), type 2 diabetes (12,13), growth factor dysregulation (14), polycystic kidney disease (15), atherosclerosis (16) and cystic fibrosis (17). However, most significantly, defects in GSL catabolism lead to toxic accumulation of GSL substrates and the GSL lysosomal storage disease (LSD) pathologies, a subclass of disorders within the 40 known LSDs (18).…”

Computer-Aided Design of Novel HIV-1 Entry Inhibitors Based on Glycosphingolipids

“…В частности, исследования -амилоидного и PrP пептидов, использующих β-GalCer для проникновения в клетку-мишень, показали [36,37], что ключевую роль в связывании играют XH···π взаимодействия углеводной части гликолипида с остатками их ароматических аминокислот. Вероятно, именно этот тип взаимодействий, наблюдаемых в структурных комплексах модифицированных форм β-GalCer с петлей V3 (табл.…”