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.

Structure Dependent Differential Modulation of Aß Fibrillization by Selenadiazole-Based Inhibitors.

Misfolding and fibrillar aggregation of Aß is a characteristic hallmark of Alzheimer's disease and primarily participates in neurodegenerative pathologies. There has been no breakthrough made in the therapeutic regime of Alzheimer's disease while the pharmacological interventions against Aß are designed to sequester and clear Aß burden from the neurological tissues. Based on the physiological relevance of Aß, therapeutic approaches are required to inhibit and stabilize Aß fibrillization, instead of cleaning it from the neurological system. In this context, we have designed a selenadiazole-based library of compounds against the fibrillization paradigm of Aß. Compounds that completely inhibited the Aß fibrillization appeared to stabilize Aß at the monomeric stage as indicated by ThT assay, CD spectrophotometry, and TEM imaging. Partial inhibitors elongated the nucleation phase and allowed limited fibrillization of Aß into smaller fragments with slightly higher ß-sheets contents, while noninhibitors did not interfere in Aß aggregation and resulted in mature fibrils with fibrillization kinetics similar to Aß control. Molecular docking revealed the different binding positions of the compounds for three classes. Complete inhibitors alleviated Aß toxicity to SH-SY5Y neuroblastoma cells and permeated across the blood-brain barrier in zebrafish larvae. The amino acid residues from Aß peptide that interacted with the compounds from all three classes were overlapping and majorly lying in the amyloidogenic regions. However, compounds that stabilize Aß monomers displayed higher association constants (Ka) and lower dissociation constants (Kd) in comparison to partial and noninhibitors, as corroborated by ITC. These results support further structure activity-based preclinical development of these selenadiazole compounds for potential anti-Alzheimer's therapy.