The Effect of Aβ on IAPP Aggregation at 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 pancreatic β-cells and a membrane damaging effect of IAPP to the β-cell membrane has been discussed as a reason for β-cell dysfunction and the development of type 2 diabetes mellitus (T2DM), the interaction of IAPP with the β-cell membrane is of high biological relevance. The interaction of Aβ and of the IAPP/Aβ mixture with β-cell membrane was investigated as an increased risk for Alzheimer disease patients to develop T2DM is given and vice versa, together with a high sequence similarity of the triggering peptides Aβ and IAPP. Details about the underlying mechanisms and the IAPP/Aβ cross interaction in the presence of membranes are still largely unknown, however. We isolated membrane lipids from the rat insulinoma-derived INS-1E β-cell line and studied the interaction of the amyloidogenic peptides IAPP, Aβ and a mixture of both peptides with the isolated membrane system. To yield insight into the peptides’ conformational changes as well as into the peptides’ effect to the membrane integrity during aggregation, we used attenuated total reflection Fourier-Transform Infrared (ATR-FTIR) spectroscopy and fluorescence microscopy. Furthermore, the time evolution of the cross interaction of IAPP and Aβ at a nanometre scale was studied by atomic force microscopy (AFM). Significant differences were found for the IAPP/Aβ mixture compared to the individual membrane-associated aggregation propensity. The IAPP/Aβ heterocomplexes formed are shown to adsorb, aggregate and permeabilize the isolated β-cell membrane system slower than pure IAPP, however, at a rate that is much faster than that of pure Aβ.