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.
Highlights
The gut microbiome is essential for regulating the homeostasis in the body and plays subtle to pivotal roles in the pathogeneses of a wide range of human disorders, from dementia and inflammation to obesity, depression, and cancer.[1,2,3,4] The relevance of the gut–brain axis to human health has been proposed for more than a decade,[5] and has recently come to the fore as a mainstream paradigm in the study of neurological disorders
As bacterial endotoxins and bacterial amyloid fragments possess realistic possibilities of accessing the brain via gastric autonomic innervation,[9,10] and crossing the compromised gut-blood barrier and the blood-brain barrier,[36,37,38] especially for those having gut infections and/or aged population groups, here we examined the cross-seeding capacity of FapC, a major protein constituent of the extracellular amyloid matrix of bacteria Pseudomonas aeruginosa, for amyloid β (Aβ) (Scheme 1)
In vivo cross-seeding was studied by coinjecting FapC seeds (FapCS) and Aβ to the cerebroventricular space of larval and adult zebrafish
Summary
The gut microbiome is essential for regulating the homeostasis in the body and plays subtle to pivotal roles in the pathogeneses of a wide range of human disorders, from dementia and inflammation to obesity, depression, and cancer.[1,2,3,4] The relevance of the gut–brain axis to human health has been proposed for more than a decade,[5] and has recently come to the fore as a mainstream paradigm in the study of neurological disorders. While resemblances in sequence and aggregation state seemingly play a role, the molecular mechanisms of cross-seeding amyloid proteins remain crucially lacking.[33,34,35] As bacterial endotoxins and bacterial amyloid fragments possess realistic possibilities of accessing the brain via gastric autonomic innervation,[9,10] and crossing the compromised gut-blood barrier and the blood-brain barrier,[36,37,38] especially for those having gut infections and/or aged population groups, here we examined the cross-seeding capacity of FapC, a major protein constituent of the extracellular amyloid matrix of bacteria Pseudomonas aeruginosa, for Aβ (Scheme 1). Our results collectively implicated that FapC seeds (FapCS) propagated their structural characteristics and acted as a catalyst for promoting Aβ amyloidogenesis in vitro, in silico and in a zebrafish AD model
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