Alzheimer's Progenitor Amyloid-ß Targets and Dissolves Microbial Amyloids and Impairs Biofilm Function.

Alzheimer's disease (AD) is a leading form of dementia where the presence of extra-neuronal plaques of Amyloid-ß (Aß) is a pathological hallmark. However, Aß peptide is also observed in the intestinal tissues of AD patients and animal models. In this study, it is reported that Aß monomers can target and disintegrate microbial amyloids of FapC and CsgA formed by opportunistic gut pathogens, Pseudomonas aeruginosa and Escherichia coli, explaining a potential role of Aß in the gut-brain axis. Employing a zebrafish-based transparent in vivo system and whole-mount live-imaging, Aß is observed to diffuse into the vasculature and subsequently localize with FapC or CsgA fibrils that were injected into the tail muscles of the fish. FapC aggregates, produced after Aß treatment (Faß), present selective toxicity to SH-SY5Y neuronal cells while the intestinal Caco-2 cells are shown to phagocytose Faß in a non-toxic cellular process. After remodeling by Aß, microbial fibrils lose their native function of cell adhesion with intestinal Caco-2 cells and Aß dissolves and detaches the microbial fibrils already attached to the cell membrane. Taken together, this study strongly indicates an anti-biofilm role for Aß monomers that can help aid in the future development of selective anti-Alzheimer's and anti-infective medicine.

Sequence-targeted Peptides Divert Functional Bacterial Amyloid Towards Destabilized Aggregates and Reduce Biofilm Formation.

Functional bacterial amyloid provides structural stability in biofilm, making it a promising target for anti-biofilm therapeutics. Fibrils formed by CsgA, the major amyloid component in E. coli are extremely robust and can withstand very harsh conditions. Like other functional amyloids, CsgA contains relatively short aggregation-prone regions (APR) which drive amyloid formation. Here, we demonstrate the use of aggregation-modulating peptides to knock down CsgA protein into aggregates with low stability and altered morphology. Remarkably, these CsgA-peptides also modulate fibrillation of the unrelated functional amyloid protein FapC from Pseudomonas, possibly through recognition of FapC segments with structural and sequence similarity with CsgA. The peptides also reduce the level of biofilm formation in E. coli and P. aeruginosa, demonstrating the potential for selective amyloid targeting to combat bacterial biofilm.