Alzheimer’s disease (AD) and type 2 diabetes (T2D) are the two common protein aggregation diseases. Increasing evidence from clinical and epidemiological studies implies that these two diseases may have intrinsic functional link via the cross-sequence interactions between β-amyloid peptide (Aβ) associated with AD and human islet amyloid polypeptide (hIAPP) with T2D. However, little is known about how these two peptides work and how they interact with each other to induce amyloidogensis. In this work, we study the effect of cross-sequence interactions between Aβ and hIAPP peptides on hybrid amyloid structures and aggregation kinetics using combined biophysics experiments and simulations (ThT, AFM, CD, and molecular dynamics). Aβ and IAPP show 25% sequence identity and 50% sequence similarity, and their fibrillar structures adopt very similar U-bend conformations. ThT and AFM results revealed that Aβ and hIAPP can interact with each other to aggregate into hybrid amyloid fibrils, with typical β-sheet-rich structures. As compared to the homo-aggregation process of either Aβ or hIAPP alone at the same peptide concentration, the hetero-aggregation process showed slow aggregation kinetics at the initial nucleation stage, but eventually resulting in more hybrid fibrils being formed. CD spectroscopy and molecular dynamics data showed that the cross-sequence interactions between Aβ and hIAPP promoted structural transition of both Aβ and hIAPP from alpha-helix to β-sheet structures. In align with cross-sequence interaction between hIAPP and rIAPP, this finding suggest that molecular recognition between Aβ, hIAPP and likely other amyloid peptides could modulate cross-amyloid, hetero-assembly, which may interpret the clinical and epidemiological links between different amyloid diseases.

Effects of cross-sequence interaction between β-amyloid and human islet amyloid polypeptide on the structure and aggregation of amyloids

249th National Meeting (2015)

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