The Effect of Aβ on IAPP Aggregation in the Presence of an Isolated β-Cell Membrane

Abstract

Fibrillar aggregates of the islet amyloid polypeptide (IAPP) and amyloid-β (Aβ) are known to deposit at pancreatic β-cells and neuronal cells, and are associated with the cell degenerative diseases type-2 diabetes mellitus (T2DM) and Alzheimer's disease (AD), respectively. Since IAPP is secreted by β-cells and a membrane damaging effect of IAPP has been discussed as a reason for β-cell dysfunction and the development of T2DM, studies of the interaction of IAPP with the β-cell membrane are of high relevance for gaining a molecular level understanding of the underlying mechanism. Recently, it has also been shown that patients suffering from T2DM exhibit an increased risk to develop Alzheimer's disease and vice versa, and a molecular link between AD and T2DM has been suggested. In this study, membrane lipids from the rat insulinoma-derived INS-1E β-cell line were isolated and their interaction with the amyloidogenic peptides IAPP, Aβ, and a mixture of both peptides has been studied. To yield insight into the associated peptides' conformational changes as well as into their effect on the membrane integrity during aggregation, ATR-FTIR spectroscopy, fluorescence microscopy, and AFM experiments have been carried out. The IAPP-Aβ heterocomplexes formed were shown to adsorb, aggregate, and permeabilize the isolated β-cell membrane significantly slower than pure IAPP, however, at a rate that is much faster than that of pure Aβ. In addition, it could be shown that isolated β-cell membranes cause similar effects on the kinetics of IAPP and IAPP-Aβ fibril formation as anionic heterogeneous model membranes.

Islet amyloid polypeptide toxicity and membrane interactions

“…The importance of postion-18 is consistent with NMR studies of IAPP fragments in the presence of model membranes (45). hIAPP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] and rIAPP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] , which differ only in the identity of residue-18, bind membranes in different orientations, and these differences are believed to correlate with the difference in the potential for membrane disruption (45,46). In summary, our data dissociate IAPP-induced leakage of standard model membranes from direct cellular toxicity, thereby indicating that further studies to identify the precise mechanism (s) of IAPP cellular toxicity are essential for the optimal development of therapeutic strategies to prevent T2D and islet graft failure.…”

“…However, these systems are notably different from the β-cell membrane, and their physiological relevance is not clear. The content of anionic lipid in model membranes typically ranges from 20 to 50 mol %, which is significantly higher than the 2.5-13.2 mol % reported for pancreatic β cells (14,15,18). Furthermore, the phospholipid composition of β-cell membranes is different from model membranes.…”

Lysophosphatidylcholine modulates the aggregation of human islet amyloid polypeptide

“…40,41 A more comprehensive description of the DMD algorithm was published elsewhere. 27 In brief, the united-atom model represents all molecules where all heavy atoms and polar hydrogen atoms are explicitly modeled. An implicit solvent model was adopted in our system.…”

“…At concentrations above the CMC, such as in the blood, LPC molecules render ultra-small micelles (~4 nm in diameter) 25,26 in size similar to that of sodium dodecyl sulfate (SDS). From the perspective of a model membrane the zwitterionic LPC micelles mimic the largely neutral pancreatic β-cell membranes (97.5% neutral, plus 2.5% anionic lipids) 27 more closely than the anionic SDS that has been used as a model system for examining protein-membrane interactions.…”

Islet Amyloid Polypeptide Membrane Interactions: Effects of Membrane Composition

“…The β-cell membrane contains cholesterol, gangliosides, sphingomyelins, and the level of anionic phospholipids is reported to range from 2.5 to 13.2 mole percent of the total phospholipids 57 . The vast majority of model systems typically contain a much higher percentage of anionic lipids and lack cholesterol and gangliosides, although the effects of cholesterol have been examined in a subset of systems 52, 57–59 . Cholesterol is an important component of membranes; it modulates their biophysical properties and is important for the uptake of hIAPP in vivo 58, 60 .…”