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.
Highlights
Alzheimer’s disease is a neurodegenerative pathology of the central nervous system currently affecting more than 25 millions of individuals worldwide
In a first set of experiments we investigated the interaction of Ab1–40 with GalCer-hydroxy (2-OH) fatty acid (HFA) (Figure 1a) and GalCer-nonhydroxy fatty acid (NFA) (Figure 1b) purified from bovine brain
The biochemical diversity of GSLs in their ceramide moiety, especially the hydroxylation status of the C2 in the acyl chain, has not been appreciated in Ab-GSLs binding studies. We believe that this issue is critical for at least three reasons: i) quantitatively, NFA and HFA species of the same GSL can be expressed in roughly similar amounts in brain tissues, as it is the case for GalCer in myelin [35]; ii) the 2-OH group has a major impact of the conformation of the GSL, due to intramolecular Hbonding possibilities [36]; iii) gender-specific expression of NFA vs. HFA ceramides have been observed in a mouse model of Alzheimer’s disease, and this biochemical feature could be related to the increased propensity of women to develop Alzheimer’s disease [37]
Summary
Alzheimer’s disease is a neurodegenerative pathology of the central nervous system currently affecting more than 25 millions of individuals worldwide. It is characterized by the presence of neuritic plaques and neurofibrillary tangles which contribute to neuronal and synaptic loss. The most abundant forms of Ab are 40- and 42-amino acid peptides respectively referred to as Ab1–40 and Ab1–42. Both peptides are found in amyloid plaques that, according to the amyloid cascade hypothesis [2,4], eventually lead to the neurodegeneration. Non-fibrillar oligomers of Ab are toxic [5], and it is difficult to assess which molecular species among dimers, oligomers and fibrils are the most pathogenic
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