Elucidating the Mechanism of Lipid Membrane-Induced IAPP Fibrillogenesis and Its Inhibition by the Red Wine Compound Resveratrol: A Synchrotron X-ray Reflectivity Study

Abstract

The islet amyloid polypeptide (IAPP) or amylin is a pancreatic hormone and crucially involved in the pathogenesis of type-II diabetes mellitus (T2DM). Aggregation and amyloid formation of IAPP is considered as the primary culprit for pancreatic beta-cell loss in T2DM patients. In this study, first X-ray reflectivity (XRR) measurements on IAPP at lipid interfaces have been carried out, providing a molecular level characterization of the first steps of the lipid-induced fibrillation process of IAPP, which is initiated by lipid-induced nucleation, oligomerization, followed by detachment of larger IAPP aggregate structures from the lipid membrane, and terminated by the formation of mature fibrils in the bulk solution. The adsorption process of IAPP at lipid interfaces in the absence and presence of negatively charged lipid has also been studied by complementary ATR-FTIR spectroscopic measurements. The morphological properties were followed by atomic force microscopy (AFM). Moreover, we show that the polyphenolic red wine compound resveratrol is able to inhibit IAPP aggregation also in the presence of aggregation-fostering negatively charged lipid interfaces, revealing its potential as a drug candidate for T2DM.

The Molecular Basis of Distinct Aggregation Pathways of Islet Amyloid Polypeptide

“…It was previously shown that a phenolic compound, resveratrol, which is abundant in red wine, can inhibit IAPP aggregation on the surface of negatively charged membranes (57). Here we demonstrated that resveratrol retards aggregation of IAPP by binding to His-18 and inhibiting early formation of oligomeric intermediates.…”

Human islet amyloid polypeptide at the air–aqueous interface: a Langmuir monolayer approach

“…This is probably due to the electrostatic repulsion of the positively charged hIAPP molecules. However, as previous studies have shown, the conformation of hIAPP changed from a-helix to b-sheet with the presence of negatively charged phospholipid, while no obvious structural changes were observed with the presence of neutral phospholipid [15,24,25]. This suggested that the attraction between the negatively charged phospholipid and positively charged hIAPP might play a critical role to accelerate or catalyse the aggregation of hIAPP.…”

“…Recent progress in the study of hIAPP and the phospholipid membrane model shows that the electrostatic interaction between the positively charged hIAPP and negatively charged phospholipid model accelerates the aggregation of hIAPP [13,16,[21][22][23][24][25][26]. In the presence of such lipids, hIAPP fibrils form within a few minutes, whereas no fibrils are observed on a neutral phospholipid [22].…”

Inhibition of Amyloid-like Fibril Formation of Trypsin by Red Wines

“…Red wine represents a rich source of polyphenols such as flavonoids (flavanol *Address correspondence to this author at the Department of Biochemistry and Molecular Biology, Faculty of Science and Informatics, University of Szeged, H-6726 Szeged, Középfasor 52, Hungary; Tel: +36-62-544543; Fax: +36-62-544887; E-mail: kotorman@expbio.bio.u-szeged.hu monomers, condensed tannins, flavonols, anthocyanins) as well as non-flavonoids (hydroxycinnamates, benzoic acids, hydrolyzable tannins and stilbenes (resveratrol)) [8]. Resveratrol, a polyphenolic red wine constituent, inhibits Aβ42 fibril formation and islet amyloid polypeptide aggregation in a dose-dependent manner [9][10]. The inhibitory effect of flavone derivatives is dependent on the number and position of hydroxyl groups around the flavone backbone [11].…”