Islet amyloid polypeptide fibril catalyzes amyloid-β aggregation by promoting fibril nucleation rather than direct axial growth

Aberrant aggregation of amyloid-beta (A beta) and islet amyloid polypeptide (IAPP) into amyloid fibrils underlies the pathogenesis of Alzheimer's disease (AD) and type 2 diabetes (T2D), respectively. T2D significantly increases AD risk, with evidence suggesting that IAPP and A beta co-aggregation and cross-seeding might contribute to the crosstalk between two diseases. Experimentally, preformed IAPP fibril seeds can accelerate A beta aggregation, though the cross-seeding mechanism remains elusive. Here, we computationally demonstrated that A beta monomer preferred to bind to the elongation ends of preformed IAPP fibrils. However, due to sequence mismatch, the A beta monomer could not directly grow onto IAPP fibrils by forming multiple stable beta-sheets with the exposed IAPP peptides. Conversely, in our control simulations of self-seeding, the A beta monomer could axially grow on the A beta fibril, forming parallel in-register beta-sheets. Additionally, we showed that the IAPP fibril could catalyze A beta fibril nucleation by promoting the formation of parallel in-register beta-sheets in the C-terminus between bound A beta peptides. This study enhances our understanding of the molecular interplay between A beta and IAPP, shedding light on the cross-seeding mechanisms potentially linking T2D and AD. Our findings also underscore the importance of clearing IAPP deposits in T2D patients to mitigate AD risk.