Cholesterol modulates the interaction of the islet amyloid polypeptide with membranes

Abstract

The deposition of insoluble amyloid fibrils resulting from the aggregation of the human islet amyloid polypeptide (hIAPP) within the islet of Langerhans is a pathological feature of type 2 diabetes mellitus (T2DM). Increasing evidence indicates that biological membranes play a key role in amyloid aggregation, modulating among others the kinetics of amyloid formation, and being the target of toxic species generated during amyloid formation. In T2DM patients, elevated levels of cholesterol, an important determinant of the physical state of biological membranes, are observed in β-cells and are thought to directly impair β-cell function and insulin secretion. However, it is not known whether cholesterol enhances membrane-interaction or membrane-insertion of hIAPP. In this study, we investigated the effect of cholesterol incorporated in zwitterionic and anionic membranes. Our circular dichroism and liquid state NMR data reveal that 10-30% of cholesterol slightly affects the aggregational and conformational behaviour of hIAPP. Additional fluorescence results indicate that 10 and 20% of cholesterol slightly slow down the kinetics of oligomer and fibril formation while anionic lipids accelerate this kinetics. This behavior might be caused by differences in membrane insertion and therefore in membrane binding of hIAPP. The membrane binding affinity was evaluated using (1)H NMR experiments and our results show that the affinity of hIAPP for membranes containing cholesterol is significantly smaller than that for membranes containing anionic lipids. Furthermore, we found that hIAPP-induced membrane damage is synchronized to fibril formation in the absence and in the presence of cholesterol.

Islet Amyloid Polypeptide Membrane Interactions: Effects of Membrane Composition

“…But in this case a modest acceleration was observed. Comparison of the data presented here with this study and with previous work 51, 52, 59 highlights the high sensitivity of IAPP membrane interactions to lipid composition. In the absence of POPS, addition of 20 mole percent cholesterol to zwitterionic LUVs increased the value of T 50 by 1.5-fold relative to the value in the absence of cholesterol.…”

“…The effects of varying the mole percent of cholesterol from 0 to 40 percent in the presence of POPC have been examined 51 . We examined the effects of cholesterol on membrane-catalyzed amyloid formation as a function of the percentage of cholesterol and POPS.…”

High speed atomic force microscopy to investigate the interactions between toxic Aβ1-42 peptides and model membranes in real time: impact of the membrane composition

“…Our results Interaction between oG37C and membrane leading to a detergent effect. 49 reported the insertion of Aβ in GM1-cholesterol domains containing liposomes and highlighted the resulting structural perturbation into the internal layers of liposomes. Our observations are in accordance with this model since the interaction of oG37C with SM/POPC/Chol/GM1 membrane leads to the rupture of the membrane by a detergent effect.…”

(R)‐α‐trifluoromethylalanine containing short peptide in the inhibition of amyloid peptide fibrillation

“…Next, liquid state 1 H NMR studies were performed to measure the kinetics of depletion of monomeric soluble Aβ42 in the absence and in the presence of molecules 1 or 2 , using the same experimental conditions as for CD (in terms of temperature, buffer composition, pH). The basis for using NMR peak intensities in kinetics studies of peptide self‐assembly is simple in that as self‐assembly occurs, the intensities of peaks due to monomer decrease as a result of the conversion of the NMR‐visible monomer to NMR‐invisible assemblies . Figures A–C shows the amide/aromatic region of the 1D 1 H NMR spectra recorded in the absence and in the presence of the molecules.…”