Impaired capillary–venous drainage contributes to gliosis and demyelination in mouse white matter during aging
The progressive loss of cerebral white matter during aging contributes to cognitive decline, but whether reduced blood flow is a cause or a consequence remains debatable. Using deep multi-photon imaging in mice, we examined microvascular networks perfusing myelinated tissues in cortical layer 6 and the corpus callosum. We identified sparse, wide-reaching venules, termed principal cortical venules, which exclusively drain deep tissues and resemble the vasculature at the human cortex and U-fiber interface. Aging led to selective constriction and rarefaction of capillaries in deep branches of principal cortical venules. This resulted in mild hypoperfusion that was associated with microgliosis, astrogliosis and demyelination in deep tissues, but not the upper cortex. Induction of comparable hypoperfusion in adult mice using carotid artery stenosis triggered a similar tissue pathology specific to layer 6 and the corpus callosum. Thus, impaired capillary-venous drainage is a contributor to hypoperfusion and a potential therapeutic target for preserving blood flow to white matter during aging.
Authors
- Hannah Bennett (ORCID: https://orcid.org/0000-0002-8939-3714)
- Kevin Takasaki (ORCID: https://orcid.org/0009-0000-1531-6022)
- Stefan Stamenković (ORCID: https://orcid.org/0000-0002-3443-9156)
- Yongsoo Kim (ORCID: https://orcid.org/0000-0002-4277-0279)
- Franca Schmid (ORCID: https://orcid.org/0000-0002-0689-9366)
- Farzaneh Abolmaali (ORCID: https://orcid.org/0000-0001-7195-8900)
- Maria J. Sosa
- Jack Waters (ORCID: https://orcid.org/0000-0002-2312-4183)
- Stephanie Bonney (ORCID: https://orcid.org/0000-0002-9519-9272)
- Andy Y. Shih (ORCID: https://orcid.org/0000-0002-7839-392X)
- Gökçe Gürler (ORCID: https://orcid.org/0000-0003-3073-4438)
- Nicolas A. Weitermann
Institutions
- University of Bern (CH)
- Seattle Children's Hospital (US)
- Pennsylvania State University (US)
- Allen Institute for Brain Science (US)
- University of Washington (US)
- Seattle Children's Hospital (US)
- Allen Institute (US)
- University of Colorado Anschutz Medical Campus (US)
- Penn State Milton S. Hershey Medical Center (US)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2025-08-12
- DOI
- https://doi.org/10.1038/s41593-025-02023-z
- Citations
- 6
- Primary Topic
- Barrier Structure and Function Studies
- Type
- article
- Field-Weighted Citation Impact
- 5.05
Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institutes of Health
- National Institute on Aging
- National Institute of Neurological Disorders and Stroke