Polymorphic cross-seeding amyloid assemblies of amyloid-β and human islet amyloid polypeptide.

Epidemiological studies have shown that the development of Alzheimer's disease (AD) is associated with type 2 diabetes (T2D), but it still remains unclear how AD and T2D are connected. Heterologous cross-seeding between the causative peptides of Aβ and hIAPP may represent a molecular link between AD and T2D. Here, we computationally modeled and simulated a series of cross-seeding double-layer assemblies formed by Aβ and hIAPP peptides using all-atom and coarse-gained molecular dynamics (MD) simulations. The cross-seeding Aβ-hIAPP assemblies showed a wide range of polymorphic structures via a combination of four β-sheet-to-β-sheet interfaces and two packing orientations, focusing on a comparison of different matches of β-sheet layers. Two cross-seeding Aβ-hIAPP assemblies with different interfacial β-sheet packings exhibited high structural stability and favorable interfacial interactions in both oligomeric and fibrillar states. Both Aβ-hIAPP assemblies displayed interfacial dehydration to different extents, which in turn promoted Aβ-hIAPP association depending on interfacial polarity and geometry. Furthermore, computational mutagenesis studies revealed that disruption of interfacial salt bridges largely disfavor the β-sheet-to-β-sheet association, highlighting the importance of salt bridges in the formation of cross-seeding assemblies. This work provides atomic-level information on the cross-seeding interactions between Aβ and hIAPP, which may be involved in the interplay between these two disorders.