Exogenous Amyloid Sequences: Their Role in Amyloid-Beta Heterotypic Aggregation

Protein aggregation is a complex process influenced by environmental conditions and interactions between multiple molecules, including those of exogenous origin. Although in vitro simulations of aggregation are crucial for advancing research, few studies explore cross-seeding as a repeating event, despite the potential for such events when proteins circulate through the body. Here, we investigated the impact of exogenous amyloid sequences derived from the gut microbiota on the heterotypic aggregation of Aβ peptides. We utilized ten 21-amino acid peptides derived from bacterial genomes, previously shown to interfere with Aβ40 aggregation and induce memory loss in Caenorhabditis elegans . Through consecutive cross-seeding assays with Aβ40 and Aβ42, we analyzed the effects of these peptides on aggregation kinetics and seed propagation. Our findings indicate that exogenous molecules can influence Aβ’s aggregation process, altering the fibrils’ properties. Based on this, we introduce the “Interaction History” concept, where prior interactions shape the aggregation and propagation of Aβ peptides. This work supports the idea that environmental factors, such as microbial amyloids, can contribute to the heterogeneity and progression of amyloid-related diseases. Our results highlight the need for therapeutic strategies targeting diverse amyloid configurations and underscore the importance of considering exogenous sequences as additional triggers in AD pathology.