Mechanistic insights into the role of amyloid-β in innate immunity

Abstract

Colocalization of microbial pathogens and the β-amyloid peptide (Aβ) in the brain of Alzheimer’s disease (AD) patients suggests that microbial infection may play a role in sporadic AD. Aβ exhibits antimicrobial activity against numerous pathogens, supporting a potential role for Aβ in the innate immune response. While mammalian amyloid is associated with disease, many bacteria form amyloid fibrils to fortify the biofilm that protects the cells from the surrounding environment. In the microbial AD hypothesis, Aβ aggregates in response to infection to combat the pathogen. We hypothesize that this occurs through toxic Aβ oligomers that contain α-sheet structure and form prior to fibrillization. De novo designed α-sheet peptides specifically bind to the α-sheet structure present in the oligomers of both bacterial and mammalian amyloidogenic proteins to neutralize toxicity and inhibit aggregation. Here, we measure the effect of E. coli on Aβ, including upregulation, aggregation, and toxicity. Additionally, we determined the effect of Aβ structure on E. coli amyloid fibrils, or curli comprised of the CsgA protein, and biofilm formation. We found that curli formation by E. coli increased Aβ oligomer production, and Aβ oligomers inhibited curli biogenesis and reduced biofilm cell density. Further, curli and biofilm inhibition by Aβ oligomers increased E. coli susceptibility to gentamicin. Toxic oligomers of Aβ and CsgA interact via α-sheet interactions, neutralizing their toxicity. These results suggest that exposure to toxic oligomers formed by microbial pathogens triggers Aβ oligomer upregulation and aggregation to combat infection via selective interactions between α-sheet oligomers to neutralize toxicity of both species with subsequent inhibition of fibrillization.

Amyloid peptide – synthetic polymer blends with enhanced mechanical and biological properties

“…1 Emerging research has uncovered non-pathological roles for amyloids in cellular systems, highlighting their unique mechanical stability and biophysical and biochemical properties. [2][3][4][5] Functional bacterial amyloids, such as the CsgA protein from Escherichia coli and the FapC protein from Pseudomonas, are examples of amyloids that serve as critical structural components in bacterial biofilms to protect the microorganism. [6][7][8] Other than cell-to-cell adhesion 9 and cell-to-host adhesion, 10 some functional amyloids and their synthetic analogues have proven to adhere strongly to abiotic surfaces.…”