Brain endothelial Gαq/11 signalling in cerebrovascular function and cognition of aged mice
BACKGROUND: signalling pathway might influence cSVD-related pathology. METHODS: signalling and characterised these mice using different imaging and staining techniques, as well as behaviour tests measuring cognition in adult and aged mice. Immunoblots, electrophysiology, perfusion measurements, and in vitro experiments complemented those techniques. FINDINGS: signalling led to capillary rarefaction and blood-brain barrier disruption in aged mice. These effects were accompanied by disturbed VEGF signalling and an increase in senescence markers and oxidative stress in the vasculature, culminating in cognitive impairment with increased tau phosphorylation in the cortex and hippocampus and decreased myelination in the white matter. INTERPRETATION: in endothelial cells in ageing. Furthermore, our results show that the combination of cerebral endothelial dysfunction and ageing accelerates cognitive impairment. FUNDING: Research was supported by grants from the European Research Council, the Deutsche Forschungsgemeinschaft, the institutional priority program MI-VascAD of the University of Lübeck, and the Marie-Sklodowska-Curie European Union's Horizon 2020 research program.
Authors
- Helge Müller‐Fielitz (ORCID: https://orcid.org/0000-0003-2815-4426)
- Thomas A. Longden (ORCID: https://orcid.org/0000-0002-7950-7677)
- Dimitrios Spyropoulos (ORCID: https://orcid.org/0000-0003-0634-4448)
- Nina Wettschureck (ORCID: https://orcid.org/0000-0001-6858-1460)
- Beate Lembrich
- Dorothea Ziemens
- Jan Sedlacik (ORCID: https://orcid.org/0000-0003-3125-1083)
- Ümit Özorhan (ORCID: https://orcid.org/0000-0002-7661-2818)
- Evi Kostenis (ORCID: https://orcid.org/0000-0001-8284-5514)
- Rentsenkhand Natsagdorj
- Gereon Hüttmann (ORCID: https://orcid.org/0000-0002-5051-3037)
- Jens Fiehler (ORCID: https://orcid.org/0000-0001-8533-7478)
- Cathrin E. Hansen (ORCID: https://orcid.org/0000-0001-7504-9413)
- Jan Wenzel (ORCID: https://orcid.org/0000-0001-6313-2439)
- Ákos Menyhárt (ORCID: https://orcid.org/0000-0002-1355-3208)
- Stefan Offermanns (ORCID: https://orcid.org/0000-0001-8676-6805)
- Phillip Ehrich
- Peter Ludewig (ORCID: https://orcid.org/0000-0001-9025-6402)
- Géza Adam Curley
- Anne-Sophie Gutt
- Lena Kleindienst
- Eszter Farkas (ORCID: https://orcid.org/0000-0002-8478-9664)
- Nicholas Noll
- Markus Schwaninger
- Ruben Nogueiras
- Vincent Prevot
Institutions
- University of Maryland, Baltimore (US)
- University of Bonn (DE)
- Inserm (FR)
- Universität Hamburg (DE)
- Universidade de Santiago de Compostela (ES)
- University of Szeged (HU)
- Université de Lille (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- Max Planck Institute for Heart and Lung Research (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Technical University of Applied Sciences Lübeck (DE)
- Instituto de Investigación Sanitaria de Santiago (ES)
- European Genomic Institute for Diabetes (FR)
- University of Lübeck (DE)
Publication Details
- Journal
- EBioMedicine
- Published
- 2026-05-18
- DOI
- https://doi.org/10.1016/j.ebiom.2026.106283
- Primary Topic
- Phosphodiesterase function and regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsche Forschungsgemeinschaft
- Universität zu Lübeck
- HORIZON EUROPE Framework Programme
- HORIZON EUROPE Marie Sklodowska-Curie Actions