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Effects of Charged Cholesterol Derivatives on A?40 Amyloid Formation.

ABSTRACT: Understanding of the mechanistic progess of amyloid-? peptide (A?) aggregation is critical for elucidating the underlying pathogenesis of Alzheimer's disease (AD). Herein, we report for the first time the effects of two cholesterol derivatives, negatively charged cholesterol sulfate (cholesterol-SO4) and positively charged 3?-[N-(dimethylaminoethane)carbamoyl]-cholesterol (DC-cholesterol), on the fibrillization of A?40. Our results demonstrate that both of the nonvesicular forms of cholesterol-SO4 and DC-cholesterol moderately accelerate the aggregation rate of A?40. This effect is similar to that observed for unmodified cholesterol, indicating the importance of hydrophobic interactions in binding of A?40 to these steroid molecules. Furthermore, we show that the vesicles formed at higher concentrations of anionic cholesterol-SO4 facilitate A?40 aggregation rate markedly. In contrast, the cationic DC-cholesterol vesicles show the ability to inhibit A?40 fibril formation under appropriate experimental conditions. The results suggest that the electrostatic interactions between A?40 and the charged vesicles can be of great importance in regulating A?40-vesicle interaction. Our results also indicate that the structural properties of the aggregates of the cholesterol derivatives, including the surface charge and the size of the vesicles, are critical in regulating the effects of these vesicles on A?40 aggregation kinetics.

SUBMITTER: Elbassal EA

PROVIDER: S-EPMC4959543 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Effects of Charged Cholesterol Derivatives on Aβ40 Amyloid Formation.

Elbassal Esmail A EA Liu Haiyang H Morris Clifford C Wojcikiewicz Ewa P EP Du Deguo D

The journal of physical chemistry. B 20151223 1

Understanding of the mechanistic progess of amyloid-β peptide (Aβ) aggregation is critical for elucidating the underlying pathogenesis of Alzheimer's disease (AD). Herein, we report for the first time the effects of two cholesterol derivatives, negatively charged cholesterol sulfate (cholesterol-SO4) and positively charged 3β-[N-(dimethylaminoethane)carbamoyl]-cholesterol (DC-cholesterol), on the fibrillization of Aβ40. Our results demonstrate that both of the nonvesicular forms of cholesterol-S ...[more]

PMID: 26652010

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Project description: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.

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Effects of Charged Cholesterol Derivatives on A?40 Amyloid Formation.

Publications

Effects of Charged Cholesterol Derivatives on Aβ40 Amyloid Formation.

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