Oral Microbiome–Derived Proteins in Brain Extracellular Vesicles Circulate and Tie to Specific Dysbiotic and Neuropathological Profiles in Age-Related Dementias
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.
Authors
- Alex Mira (ORCID: https://orcid.org/0000-0002-9127-3877)
- Anna Lagunas (ORCID: https://orcid.org/0000-0002-0936-3401)
- Xavier Gallart‐Palau (ORCID: https://orcid.org/0000-0001-5160-8794)
- María‐Victoria Mateos‐Moreno (ORCID: https://orcid.org/0000-0002-8237-4596)
- María Mulet (ORCID: https://orcid.org/0009-0002-8239-7015)
- Raj N. Kalaria (ORCID: https://orcid.org/0000-0001-7907-4923)
- José Antonio Sánchez Milán (ORCID: https://orcid.org/0009-0007-1319-1298)
- Amado Cruz Crespo
- María Fernández‐Rhodes (ORCID: https://orcid.org/0000-0002-9262-7147)
- Aida Serra (ORCID: https://orcid.org/0000-0002-4017-1096)
- Laura Saiz
- Josep Samitier (ORCID: https://orcid.org/0000-0002-1140-3679)
- Alberto Rábano (ORCID: https://orcid.org/0000-0001-9320-6566)
- Cristina Lorca (ORCID: https://orcid.org/0000-0002-7975-3691)
- Yoshiki Hase (ORCID: https://orcid.org/0000-0002-9538-905X)
- Mònica Mir (ORCID: https://orcid.org/0000-0002-1490-8373)
- Maurício Castillo (ORCID: https://orcid.org/0000-0003-2960-1064)
- Teodoro del Ser (ORCID: https://orcid.org/0000-0001-9806-7083)
- Ana Adrados-Planell
Institutions
- Universidad Complutense de Madrid (ES)
- Instituto de Salud Carlos III (ES)
- Hospital Universitari Arnau de Vilanova (ES)
- Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (ES)
- Madrid Health Service (ES)
- Instituto de Investigación Biomédica de Lleida (ES)
- Institute for Bioengineering of Catalonia (ES)
- Newcastle Hospitals - Campus for Ageing and Vitality (GB)
- Fundacion Centro De Investigacion De Enfermedades Neurologicas (ES)
- Newcastle University (GB)
Publication Details
- Journal
- Molecular & Cellular Proteomics
- Published
- 2025-11-15
- DOI
- https://doi.org/10.1016/j.mcpro.2025.101464
- Citations
- 1
- Primary Topic
- Oral microbiology and periodontitis research
- Type
- article
- Field-Weighted Citation Impact
- 1.47