Fernandez Gallegos, M. R. | Search bioRxiv

bioRxiv2025

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 A{beta} peptides. We utilized ten 21-amino acid peptides derived from bacterial genomes, previously shown to interfere with A{beta}40 aggregation and induce memory loss in Caenorhabditis elegans. Through consecutive cross-seeding assays with A{beta}40 and A{beta}42, we analyzed the effects of these peptides on aggregation kinetics and seed propagation. Our findings indicate that exogenous molecules can influence A{beta}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 A{beta} 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 reinforce the importance of considering exogenous sequences as additional triggers in AD pathology.

biochemistry↗

bioRxiv2023

Microbiome-Derived Prion-Like Proteins and Their Potential to Trigger Cognitive Dysfunction

Our life is intricately connected to microorganisms through infection or symbiotic relationships. While the inter-species propagation of prion-like proteins is well-established, their presence in the microbiome and impact on the host remains largely unexplored. To address this, we conducted a systematic study integrating in silico, in vitro, and in vivo analyses, showing that 63% of the gastrointestinal tract microbiome encodes prion-like sequences. These sequences can form amyloid fibrils capable of interfering with the aggregation of the Amyloid-beta-peptide and promoting the aggregation and propagation of the Sup35 prion. Finally, when C. elegans were fed with bacteria expressing chimeras of our prion candidates, it resulted in the loss of sensory memory, reproducing the Alzheimers model phenotype. In our model, memory impairment is linked to aggregate fragmentation and its susceptibility to degradation. Taken together, these findings show that the gut microbiota serves as a potential reservoir of prion-like sequences, supporting the idea that microbial products may influence the pathogenesis of neurodegenerative diseases.

molecular biology↗