Abstract
Amyloid aggregates are hallmarks of the pathology of a wide range of diseases, including type 2 diabetes (T2D) and Alzheimer's disease (AD). Much epidemiological and pathological evidence points to significant overlap between AD and T2D. Individuals with T2D have a higher likelihood of developing AD; moreover, colocalized aggregates of amyloid β (Aβ) and the islet amyloid polypeptide (IAPP), the two main peptides implicated in the formation of toxic amyloid aggregates in AD and T2D, have also been identified in the brain. However, how these peptides interact with each other is not well understood, and the structural facets of heterotypic mixed fibrils formed via such interactions remain elusive. Here we use atomic force microscopy augmented with infrared spectroscopy to probe the secondary structure of individual aggregates formed via heterotypic interactions of Aβ and IAPP and provide unequivocal direct evidence of mixed aggregates. Furthermore, we show that co-aggregation of the peptides from the monomeric stage leads to the formation of unique polymorphs, in which both peptides undergo structural deviation from their native states, whereas seeding with preformed IAPP fibrils leads to aggregates similar to native Aβ. These findings highlight how heterotypic interactions between amyloidogenic peptides can lead to polymorphic diversity proteinopathies.