Computational Investigation of Co-Aggregation and Cross-Seeding between Aβ and hIAPP Underpinning the Crosstalk in Alzheimer's Disease and Type-2 Diabetes

The coexistence of Amyloid-β (Aβ) and human Islet Amyloid Polypeptide (hIAPP) in the brain and pancreas is associated with an increased risk of Alzheimer’s disease (AD) and type-2 diabetes (T2D) due to their co-aggregation and cross-seeding. Despite this, the molecular mechanisms underlying their interaction remain elusive. Here, we systematically investigated the cross-talk between Aβ and hIAPP using atomistic discrete molecular dynamics (DMD) simulations. Our results revealed that the amyloidogenic core regions of both Aβ (Aβ_10–21 and Aβ_30–41) and hIAPP (hIAPP_8-20 and hIAPP_22-29), driving their self-aggregation, also exhibited a strong tendency for cross-interaction. This propensity led to the formation of β-sheet-rich hetero-complexes, including potentially toxic β-barrel oligomers. The formation of Aβ and hIAPP hetero-aggregates did not impede the recruitment of additional peptides to grow into larger aggregates. Our cross-seeding simulations demonstrated that both Aβ and hIAPP fibrils could mutually act as seeds, assisting each other's monomers in converting into β-sheets at the exposed fibril elongation ends. The amyloidogenic core regions of Aβ and hIAPP, in both oligomeric and fibrillar states, exhibited the ability to recruit isolated peptides, thereby extending the β-sheet edges, with limited sensitivity to the amino acid sequence. These findings suggest that targeting these regions by capping them with amyloid-resistant peptide drugs may hold potential as a therapeutic approach for addressing AD, T2D, and their co-pathologies.