Accelerated Amyloid Beta Pathogenesis by Bacterial Amyloid FapC

Abstract

The gut–brain axis has attracted increasing attention in recent years, fueled by accumulating symptomatic, physiological, and pathological findings. In this study, the aggregation and toxicity of amyloid beta (Aβ), the pathogenic peptide associated with Alzheimer's disease (AD), seeded by FapC amyloid fragments (FapCS) of Pseudomonas aeruginosa that colonizes the gut microbiome through infections are examined. FapCS display favorable binding with Aβ and a catalytic capacity in seeding the peptide amyloidosis. Upon seeding, twisted Aβ fibrils assume a much‐shortened periodicity approximating that of FapC fibrils, accompanied by a 37% sharp rise in the fibrillar diameter, compared with the control. The robust seeding capacity for Aβ by FapCS and the biofilm fragments derived from P. aeruginosa entail abnormal behavior pathology and immunohistology, as well as impaired cognitive function of zebrafish. Together, the data offer the first concrete evidence of structural integration and inheritance in peptide cross‐seeding, a crucial knowledge gap in understanding the pathological correlations between different amyloid diseases. The catalytic role of infectious bacteria in promoting Aβ amyloidosis may be exploited as a potential therapeutic target, while the altered mesoscopic signatures of Aβ fibrils may serve as a prototype for molecular assembly and a biomarker for screening bacterial infections in AD.

Colonization of the Caenorhabditis elegans gut with human enteric bacterial pathogens leads to proteostasis disruption that is rescued by butyrate

“…As such, it is likely that bacteria may be secreting factors that translocate from the intestine across other tissues and affect proteostasis. A cross-seeding between disease-associated proteins (i.e., Aβ) with bacterial amyloids, including those from E. coli and P. aeruginosa, was previously observed [72,73]. Also, an enhancement of alpha-synuclein aggregation mediated by bacterial curli was shown in mouse and C. elegans Parkinson's disease models [74].…”

“…coli and P . aeruginosa , was previously observed [ 72 , 73 ]. Also, an enhancement of alpha-synuclein aggregation mediated by bacterial curli was shown in mouse and C .…”

Crosstalk between Gut and Brain in Alzheimer’s Disease: The Role of Gut Microbiota Modulation Strategies

“…CsgA shares dissimilarity in sequences with Aβ 42 but is similar in triggering AD-related pathogenic effects and promoting cerebral plaque deposition [ 81 ]. In a recent study, Javed et al [ 92 ] claimed that FapCS favorably bound with Aβ, showed a catalytic capacity in seeding peptide amyloidosis, impaired cognitive performance, and behavior pathology in vitro, in silico and in a zebrafish AD model. Additionally, phenol soluble modulins contain cross-α structure and form cross-β fibrils associated with AD [ 93 ].…”

Roles and Mechanisms of Gut Microbiota in Patients With Alzheimer’s Disease

“…Higher levels of LPS and E. coli fragment K99 can promote myelin aggregates that colocalize with Aβ and resemble amyloid-like plaques. In addition, Javed et al (2020) found that FapC amyloid fragments (FapCS) of Pseudomonas aeruginosa display favorable binding with Aβ and a catalytic capacity to seed peptide amyloidosis, contributing to the aggregation and toxicity of Aβ. The robust seeding capacity for Aβ by FapCS and the biofilm fragments derived from P. aeruginosa entailed abnormal behavior pathology and immunohistology and impaired cognitive function in zebrafish.…”