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Modulation of Amyloid-β Aggregation by Surface Proteins from Pathogens Associated with Alzheimer's Disease
Antonin Kunka1,2, Hana Hribkova3, Tereza Vanova2,3
1Loschmidt Laboratories, Department of Experimental Biology and RECETOX, Faculty of Science, Masaryk University, Brno 625 00, Czech Republic.
Abstract:
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder. Despite substantial research efforts, our understanding of its pathogenesis remains incomplete, limiting the development of effective treatments and preventive strategies. The potential role of microbial pathogens in AD etiology has gained increasing attention. Various human microbial pathogens have been identified in the brains of AD patients, leading to the pathogen hypothesis, which posits that these microorganisms may disrupt the brain's immune regulation and homeostasis. In this study, we examine the effects of proteins from three pathogens, Borrelia burgdorferi, HSV-1, and Porphyromonas gingivalis, on the aggregation of antimicrobial peptide amyloid-β (Aβ). Three of the four studied proteins were found to attenuate the aggregation of Aβ42 by interacting with its soluble form and inhibiting primary and secondary pathways. These in vitro findings were further supported by experiments using mature neurons derived from human pluripotent stem cells, which showed an increased accumulation of amyloid precursor protein (APP) aggregates upon infection with HSV-1 or exposure to the OspA surface protein from B. burgdorferi. Together, our results provide mechanistic insights into how pathogen-associated proteins modulate Aβ42 aggregation, contributing to an understanding of their potential role in AD pathogenesis.
Insights
Certain pathogen proteins may reduce amyloid-β (Aβ) aggregation, a key factor in Alzheimer's disease (AD). This research explores how microbial proteins influence Aβ42 and amyloid precursor protein (APP) in brain cells.
Area of Science:
- Neuroscience
- Microbiology
- Biochemistry
Background:
- Alzheimer's disease (AD) pathogenesis is not fully understood, hindering effective treatments.
- The pathogen hypothesis suggests microbial involvement in AD etiology.
- Microbial pathogens have been found in the brains of AD patients.
Purpose of the Study:
- To investigate the effect of pathogen-associated proteins on amyloid-β (Aβ) aggregation.
- To explore the mechanistic link between microbial proteins and AD pathology.
Main Methods:
- In vitro assays examining the interaction of pathogen proteins with Aβ42.
- Experiments using human pluripotent stem cell-derived neurons exposed to pathogen proteins or infections.
- Analysis of amyloid precursor protein (APP) aggregation.
Main Results:
- Three out of four tested pathogen proteins attenuated Aβ42 aggregation by interacting with soluble Aβ42.
- These proteins inhibited primary and secondary Aβ42 aggregation pathways.
- HSV-1 infection or exposure to Borrelia burgdorferi OspA protein increased APP aggregates in human neurons.
Conclusions:
- Pathogen-associated proteins can modulate Aβ42 aggregation, offering mechanistic insights into their potential role in AD.
- Findings support the pathogen hypothesis by demonstrating how microbial components may influence key AD pathological features.
- This study contributes to understanding the complex interplay between microbial factors and neurodegeneration in Alzheimer's disease.
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