RESUMO
Aggregation of the amyloid ß (Aß) peptide into fibrils represents one of the major biochemical pathways underlying the development of Alzheimer's disease (AD). Extensive studies have been carried out to understand the role of fibrillar seeds on the overall kinetics of amyloid aggregation. However, the precise effect of seeds that are structurally or sequentially different from Aß on the structure of the resulting amyloid aggregates is yet to be fully understood. In this work, we use nanoscale infrared spectroscopy to probe the spectral facets of individual aggregates formed by aggregating Aß42 with antiparallel fibrillar seeds of Aß (16-22) and E22Q Aß (1-40) Dutch mutant and demonstrate that Aß can form heterotypic or mixed polymorphs that deviate significantly from its expected parallel cross ß structure. We further show that formation of heterotypic aggregates is not limited to coaggregation of Aß and its isomers, and that the former can form heterotypic fibrils with alpha synuclein and brain protein lysates. These findings highlight the complexity of Aß aggregation in AD and underscore the need to explore how Aß interacts with other brain components, which is crucial for developing better therapeutic strategies for AD.
