Multi-modal choroid plexus pathology in aging and Alzheimer’s disease
Brain barriers, cerebrospinal fluid (CSF) dynamics, and peripheral factors are implicated as significant contributors to Alzheimer's disease (AD). The choroid plexus (ChP) is a blood-brain interface that produces CSF and forms the blood-CSF barrier. However, how ChP pathology develops across the lifespan and contributes to AD has not been systematically characterized. Here, we report a multi-modal ChP atlas integrating single-nucleus transcriptomics from 49 individuals, AI-assisted quantitative histopathology across >500 postmortem samples age 16 to 105, spatial transcriptomics, and functional studies in 5xFAD mice. We identify fibrosis, calcification, and macrophage abnormalities as hallmarks of ChP aging, with AD pathology conferring additional effects, including expansion of a pro-inflammatory fibroblast-macrophage signaling niche. In 5xFAD mice, macrophage dysfunction is associated with impaired epithelial barrier maintenance and repair. Together, these data provide a foundational resource for understanding ChP dysfunction in aging and AD and propose the macrophage-fibroblast-epithelial barrier axis as a driver of ChP pathology.
Authors
- Rute M. S. M. Pedrosa
- Jane Oberhauser (ORCID: https://orcid.org/0000-0001-9792-0441)
- Henri Puttonen (ORCID: https://orcid.org/0000-0002-8059-8457)
- Daniel S. Reich (ORCID: https://orcid.org/0000-0002-2628-4334)
- Tony Wyss‐Coray (ORCID: https://orcid.org/0000-0001-5893-0831)
- Jarno Tuimala
- Maria K. Lehtinen (ORCID: https://orcid.org/0000-0002-7243-2967)
- Benjamin Englert (ORCID: https://orcid.org/0000-0002-1769-5393)
- Kia Colangelo
- Caitlin S. Latimer (ORCID: https://orcid.org/0000-0003-3727-4278)
- Deidre Jansson (ORCID: https://orcid.org/0000-0001-9757-8682)
- Andrew C. Yang (ORCID: https://orcid.org/0000-0002-6756-4746)
- Liisa Myllykangas (ORCID: https://orcid.org/0000-0002-2237-5466)
- Pekka J. Karhunen (ORCID: https://orcid.org/0000-0002-0320-571X)
- Dorothy P. Schafer (ORCID: https://orcid.org/0000-0003-2201-6276)
- José Ordovás-Montañés (ORCID: https://orcid.org/0000-0001-5444-5601)
- Micaiah Atkins (ORCID: https://orcid.org/0000-0003-0068-5217)
- Terho J. Lehtimäki (ORCID: https://orcid.org/0000-0002-2555-4427)
- Aja Pragana
- Peter Lotfy (ORCID: https://orcid.org/0000-0003-0809-7073)
- Darshan Kumar (ORCID: https://orcid.org/0000-0001-5371-1779)
- Pei Lin (ORCID: https://orcid.org/0000-0002-9844-945X)
- Ashley A. Thommana (ORCID: https://orcid.org/0009-0004-1117-8987)
- Mary Elizabeth Gabrielle
- Eloise H Kok
- Katherine E Prater
- Lillian I.J. Byer
- Huixin Xu
- Alina E Isakova
- Shon Alimukhamedov
- Serhat V. Okar
- Anna Dong
- James Francis Haberberger
- Jordan Benson
- Mikko I. Mäyränpää
- C. Dirk Keene
- David M. Holtzman
- Jasmin Wihlman
- Violeta DurántLaforet
Institutions
- Broad Institute (US)
- Boston Children's Hospital (US)
- Gladstone Institutes (US)
- University of Helsinki (FI)
- Harvard University (US)
- Thomas Jefferson University (US)
- Tampere University of Applied Sciences (FI)
- University of Massachusetts Chan Medical School (US)
- Tampere University (FI)
- University of California, San Francisco (US)
- University of Washington (US)
- Helsinki Institute of Physics (FI)
- Helsinki University Hospital (FI)
- Harvard University Press (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- Raytheon Technologies (Finland) (FI)
- Neuropsychiatric Research Institute (US)
- Stanford Health Care (US)
- National Institute of Neurological Disorders and Stroke (US)
- Pirkanmaa Hospital District (FI)
- Hope Center for Neurological Disorders (US)
- Tampere University Hospital (FI)
- Tampere University (FI)
- Fimlab (Finland) (FI)
- VA Northwest Network (US)
- Harvard Stem Cell Institute (US)
- Hospital District of Helsinki and Uusimaa (FI)
- Stanford University (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2025-12-31
- DOI
- https://doi.org/10.64898/2025.12.30.697051
- Citations
- 1
- Primary Topic
- Cerebrospinal fluid and hydrocephalus
- Type
- article
- Field-Weighted Citation Impact
- 0.91
Funders
- Biocenter Finland
- Intellectual and Developmental Disabilities Research Center
- Helsinki Institute of Life Science, Helsingin Yliopisto