BPS2026 – Structural characterization of toxic hIAPP oligomers via 2D IR spectroscopy and immunosensors

The aggregation of human islet amyloid polypeptide (hIAPP) into amylin plaques is a key pathological feature of type 2 diabetes. This peptide, which is co-secreted with insulin, can transiently form cytotoxic oligomers, which permeabilize pancreatic β-cell membranes and induce cellular stress, contributing to disease progression. The structural properties of the naturally occurring oligomers remain poorly characterized due to their low-abundance, short lifetimes as well as the co-existence of monomers and oligomeric distribution present simultaneously. To directly probe the structure of these cytotoxic intermediates, we developed a gold-CaF 2 immunosensor functionalized with the monoclonal antibody α-IAPP-O, which specifically binds to the toxic oligomeric conformation of hIAPP. Using two-dimensional infrared (2D IR) spectroscopy, we obtained spectra in the amide I region of the surface-bound species, resolving vibrational signatures that report on secondary-structure. In parallel, polyclonal antibody functionalized immunosensors, which capture a broader distribution of hIAPP species, provide a comparative baseline for distinguishing monomeric and oligomeric states. Together, these strategies enable the direct study of the toxic oligomer’s structure, offering new insights into the molecular mechanisms of hIAPP toxicity. Such knowledge is critical for designing therapeutic strategies aimed at protecting pancreatic β-cells and slowing the progression of type 2 diabetes.