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.

• Keywords
• Alzheimer’s disease, amyloid-β, amyloids, neuroinflammation, pathogen, virus,
• MeSH
• Alzheimer Disease * metabolism   microbiology   MeSH
• Amyloid beta-Peptides * metabolism   MeSH
• Amyloid beta-Protein Precursor metabolism   MeSH
• Bacterial Proteins * metabolism   pharmacology   MeSH
• Borrelia burgdorferi metabolism   MeSH
• Humans MeSH
• Herpesvirus 1, Human metabolism   MeSH
• Neurons metabolism   drug effects   MeSH
• Peptide Fragments * metabolism   MeSH
• Porphyromonas gingivalis metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• amyloid beta-protein (1-42) MeSH Browser
• Amyloid beta-Peptides * MeSH
• Amyloid beta-Protein Precursor MeSH
• Bacterial Proteins * MeSH
• Peptide Fragments * MeSH