The effect of Aβ on IAPP aggregation in the presence of an isolated β-cell membrane.
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 AD 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 and Aβ and a mixture of both peptides has been studied. To yield insight into the associated peptides' conformational changes and their effect on the membrane integrity during aggregation, we have carried out attenuated total reflection Fourier transform infrared spectroscopy, fluorescence microscopy, and atomic force microscopy experiments. 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.
Physical Chemistry I-Biophysical Chemistry, Faculty of Chemistry, TU Dortmund University, Otto-Hahn-Strasse 6, 44227 Dortmund, Germany.
Janine
J
Seeliger
Katrin
K
Weise
Norbert
N
Opitz
Roland
R
Winter
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000378:metabolism; D007515:Islets of Langerhans / Q000737:chemistry* / Q000378:metabolism; D018625:Microscopy, Atomic Force; D008856:Microscopy, Fluorescence; D017550:Spectroscopy, Fourier Transform Infrared
D016229:Amyloid beta-Peptides; D058228:Islet Amyloid Polypeptide