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Lookup NU author(s): Dr Yoshiki Hase, Professor Raj KalariaORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved. The involvement of the oral microbiome (OM) in the pathophysiology of Alzheimer's disease and vascular dementia has been recognized epidemiologically, but the molecular mechanisms remain elusive. In this study, we uncovered the presence of OM-derived proteins (OMdPs) in brain extracellular vesicles (bEVs) from post-mortem Alzheimer's disease and vascular dementia subjects using unbiased metaproteomics. OMdP circulation in blood EVs was also confirmed in an independent cohort. Our findings also reveal that specific OMdPs are present in bEVs, with their levels varying with disease progression. Peptidome-wide correlation analyses further explored their exchange dynamics and composition within bEVs. In addition, we validated the ability of OM-derived EVs to cross the blood-brain barrier using a blood-brain barrier-on-a-chip model, confirming a potential route for bacterial-derived molecules to reach the central nervous system. Bioinformatics-driven interaction analyses indicated that OMdPs engage with key neuropathological proteins, including amyloid-beta and tau, suggesting a novel mechanism linking dysbiotic OM to dementia. These results provide new insights into the role of the OM in neurodegeneration and highlight OMdPs as potential biomarkers and therapeutic targets.
Author(s): Mulet M, Sanchez Milan JA, Lorca C, Fernandez-Rhodes M, Adrados-Planell A, Bejarano Castillo MC, Saiz L, Mateos-Moreno M-V, Hase Y, Mira A, Rabano A, Ser TD, Kalaria RN, Lagunas A, Mir M, Crespo A, Samitier J, Gallart-Palau X, Serra A
Publication type: Article
Publication status: Published
Journal: Molecular & Cellular Proteomics
Year: 2025
Volume: 24
Issue: 12
Print publication date: 01/12/2025
Online publication date: 12/11/2025
Acceptance date: 06/11/2025
Date deposited: 06/01/2026
ISSN (electronic): 1535-9484
Publisher: Elsevier Inc.
URL: https://doi.org/10.1016/j.mcpro.2025.101464
DOI: 10.1016/j.mcpro.2025.101464
Data Access Statement: All data utilized in this study are publicly accessible, and no new MS data were generated. Data can be accessed via the specialized repository ProteomeXchange under the accession numbers PXD015578 for bEV proteomes and WB proteomes and PXD024216 for plasma EV proteomes. The scripts created for the bioinformatic analyses performed have also been made publicly available through GitHub: https://github.com/MariaMuletFernandez/OralMicrobiome
PubMed id: 41237903
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