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BACTERIAL AMYLOID CURLI INFLUENCES AGGREGATION OF AMYLOID BETA PEPTIDES ASSOCIATED WITH ALZHEIMER ́S DISEASE

Date

2023-10-02

Journal Title

Journal ISSN

Volume Title

Publisher

ORCID

0009-0003-6321-4751

Type

Thesis

Degree Level

Masters

Abstract

Amyloid proteins are associated with various disorders such as Alzheimer's, Parkinson's, prion diseases, and type 2 diabetes. Each of these illnesses involves a specific amyloid protein or peptide that misfolds and forms fibrils. Apart from pathological amyloids, there are amyloids that are considered functional amyloids. Functional amyloids are produced by different organisms, and in contrast to pathological amyloids, they serve various biological functions. For my MSc. project I focus on the pathological amyloid-β (Aβ) associated with Alzheimer's disease and the functional amyloid curli. Curli is produced by the foodborne pathogen Salmonella and the commensal bacteria Escherichia coli. Curli is classified as a functional amyloid because it provides a structural role in the biofilm extracellular matrix. CsgA and CsgB are the curli structural components. When CsgA and CsgB reach the cell surface, they change from an unstructured state as secreted proteins to -rich structures that assemble into amyloid fibrils at the cell surface. Despite being encoded by distinct protein sequences, curli fibrils share a common 3D structure with Aβ. The mechanism of how Aβ peptides convert from soluble functional proteins into insoluble amyloid fibrils is not fully understood. Given that both proteins are naturally amyloidogenic and share a similar structural fold, the subject of my M.Sc. research is to investigate if Salmonella curli can cross-react with A peptides. The effects of curli on aggregation and aggregate cytotoxicity of Aβ(1-42) and A(1-40) peptides were investigated by a combination of biophysical (Western blot analysis and kinetic studies with thioflavin T fluorescence) and cellular assays (cell viability in male and female human fibroblasts). I demonstrate that curli can physically interact with both A peptides in vitro. The biophysical data shows that curli promotes Aβ(1-42) fibrillization and accelerate the overall aggregation of Aβ(1-40) (i.e., oligomers + fibrils). The data with cultured cells shows that Aβ(1- 42)/curli aggregates are less cytotoxic that Aβ(1-42) aggregates. Our results support mounting evidence that oligomers—as opposed to mature fibrils— are probably the more toxic species of the peptides. Although we cannot correlate our results to the complex pathology of AD yet, our findings contribute to evidence that exogenous (sometimes bacterial) amyloids may influence and cross-react with host amyloids. Moreover, the interactions shown in my work may provide new insights into the molecular mechanisms of interactions between bacterial amyloids and human amyloids.

Description

Keywords

Amyloids, curli, Salmonella, Alzheimer's Disease

Citation

Degree

Master of Science (M.Sc.)

Department

Biochemistry

Program

Microbiology and Immunology

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DOI

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