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

INTRODUCTION: The Pathogen Infection Hypothesis proposes that β-Amyloid (Aβ) functions as an antimicrobial peptide, with pathogen-induced aggregation potentially contributing to Alzheimer's disease (AD) pathology. METHODS: We used human iPSC-derived 2D neurons and 3D cerebral organoids from wild-type and familial AD (PSEN1/2 mutant) lines to model acute infections with HSV-1 and TBEV and Aβ aggregation. Transcriptomic and proteomic analyses were conducted to assess molecular responses. RESULTS: HSV-1, but not TBEV, induced robust Aβ clustering, which was, however, dependent on extracellular amyloid peptides. Transcriptomic profiling revealed widespread HSV-1-induced changes, including activation of neurodegeneration-related pathways. Proteomic profiling confirmed enrichment of neurodegeneration- and senescence-associated secretome signatures. PSEN1/2 mutations did not alter the acute infection response. Reanalysis of independent datasets confirmed our findings and revealed a limited protective effect of acyclovir. DISCUSSION: Results directly support the Pathogen Infection Hypothesis and suggest that preventing viral infections via vaccinations may represent a feasible approach to reducing AD risk.

• Keywords
• Alzheimer’s disease, Cerebral organoids, Herpes virus, Senescence, Tick-borne Encephalitis,
• Publication type
• Journal Article MeSH
• Preprint MeSH

The involvement of microRNAs (miRNAs) in orchestrating self-renewal and differentiation of stem cells has been revealed in a number of recent studies. And while in human pluripotent stem cells, miRNAs have been directly linked to the core pluripotency network, including the cell cycle regulation and the maintenance of the self-renewing capacity, their role in the onset of differentiation in other contexts, such as determination of neural cell fate, remains poorly described. To bridge this gap, we used three model cell types to study miRNA expression patterns: human embryonic stem cells (hESCs), hESCs-derived self-renewing neural stem cells (NSCs), and differentiating NSCs. The comprehensive miRNA profiling presented here reveals novel sets of miRNAs differentially expressed during human neural cell fate determination in vitro. Furthermore, we report a miRNA expression profile of self-renewing human NSCs, which has been lacking to this date. Our data also indicates that miRNA clusters enriched in NSCs share the target-determining seed sequence with cell cycle regulatory miRNAs expressed in pluripotent hESCs. Lastly, our mechanistic experiments confirmed that cluster miR-17-92, one of the NSCs-enriched clusters, is directly transcriptionally regulated by transcription factor c-MYC.

• Keywords
• Cell cycle, Human pluripotent stem cells, Neural stem cells, miRNA sequencing, microRNA,
• MeSH
• Cell Differentiation genetics   MeSH
• Embryonic Stem Cells MeSH
• Humans MeSH
• MicroRNAs * genetics   metabolism   MeSH
• Neural Stem Cells * metabolism   MeSH
• Gene Expression Profiling MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• MicroRNAs * MeSH