Heterotypic Amyloid β interactions facilitate amyloid assembly and modify amyloid structure

It is still unclear why pathological amyloid deposition initiates in specific brain regions or why some cells or tissues are more susceptible than others. Amyloid deposition is determined by the self-assembly of short protein segments called aggregation-prone regions (APRs) that favour cross-beta structure. Here, we investigated whether A beta amyloid assembly can be modified by heterotypic interactions between A beta APRs and short homologous segments in otherwise unrelated human proteins. Mining existing proteomics data of A beta plaques from AD patients revealed an enrichment in proteins that harbour such homologous sequences to the A beta APRs, suggesting heterotypic amyloid interactions may occur in patients. We identified homologous APRs from such proteins and show that they can modify A beta assembly kinetics, fibril morphology and deposition pattern in vitro. Moreover, we found three of these proteins upon transient expression in an A beta reporter cell line promote A beta amyloid aggregation. Strikingly, we did not find a bias towards heterotypic interactions in plaques from AD mouse models where A beta self-aggregation is observed. Based on these data, we propose that heterotypic APR interactions may play a hitherto unrealized role in amyloid-deposition diseases.