Heterotypic\nInteractions of Amyloid β and the\nIslet Amyloid Polypeptide Produce Mixed Aggregates with Non-Native\nFibril Structure

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