Seeding and Cross-Seeding Aggregations of Aβ40 and hIAPP in Solution and on Surface

Abstract

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM), common incurable diseases caused by protein misfolding, have shown extensive correlation with each other via cross-aggregation between their related pathogenic peptide, amyloid β protein (Aβ) and human islet amyloid polypeptide (hIAPP), respectively. However, little is known about how these two peptides affect the cross-amyloid aggregation process in vivo.To better simulate the intracorporal environment, where different forms of amyloid aggregates co-exist and very few aggregates probably attach to the vessel wall as seeds, herein, we study the seeded-aggregation of Aβ and hIAPP in the presence of homogeneous or heterogeneous seeds, both in solution and on the solid surface, with different monomer and seed concentrations. In this study, Thioflavin T (ThT) fluorescence assay, atomic force microscopy (AFM), and far-UV circular dichroism (CD) were performed to investigate the aggregation process in solution. Moreover, the binding of monomers with seeds on solid surface was detected by quartz crystal microbalance with dissipation (QCM-D). The 3-(4,5-dime-thylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays with human neuroblastoma cells (SH-SY5Y) were finally used to test the cytotoxicity caused by the aggregates. Series of analyses confirmed that a small amount of Aβ40 or hIAPP seeds (1/50 of the monomers in solution) significantly changed the aggregation pathway, forming heterogeneous aggregates with different morphologies and increased β-sheet structures. MTT result showed that the heterogeneous aggregates obtained with Aβ40 and hIAPP seeding reduced the cell viability to 70.5% and 74.4%, respectively, both causing higher cytotoxicity than homogeneous aggregates (82.9% and 76.5%, respectively). The results in solution and on the solid surface both prove that Aβ40 and hIAPP seeds can not only induce rapid aggregation of their homogeneous monomers but also promote the heterogeneous monomers to aggregate, but monomer-heterogeneous seed binding efficiency is lower than that between homogeneous species. The differences in seeding and cross-seeding ability of Aβ40 and hIAPP indicate the barriers depended on the sequence similarity and structural compatibility between different amyloid aggregates. In the case of heterogeneous aggregation, aggregation features largely depend on the seeds. Furthermore, hIAPP seeds exhibited higher cross-seeding efficiency than Aβ40 seeds on the solid surface, which is different from the result in solution where Aβ40 seeds indicating the influence of interfacial properties on aggregation process. This finding would give a deep understanding of the cross-seeding aggregation process and we hope that this work will stimulate more research to explore all possible fundamental and practical aspects of amyloid cross-seeding.

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