Reversible Hypervascularization Drives Cognitive Decline and Blood-Brain Barrier Damage During Aging
MCML Authors
Abstract
Abstract
Cerebrovascular dysfunction emerges early in neurodegeneration, yet how vascular structure, blood–brain barrier (BBB) failure, and cognition are linked remains undefined. Using VesselPro, a whole-brain pipeline integrating perfusion-resolved 3D imaging with spatial proteomics, we mapped vascular aging across the mouse lifespan. We identify two discrete trajectories: a hypovascular state and a previously unrecognized hyper-vascular, BBB-compromised state, defined relative to a young-adult vascular baseline. The hyper-vascular trajectory, concentrated in the cortex and hippocampus, was associated with marked spatial memory impairment and pervasive BBB leakage. Spatial proteomics revealed a coordinated program involving angiogenic activation, endothelial stress, cytoskeletal remodeling, and inflammatory signaling. Cross-species comparison with human proteomic biomarkers from the UK Biobank showed strong alignment between the mouse hypervascular signature and vascular dementia risk, but minimal concordance with Alzheimer’s disease, defining a vascular-specific dementia endotype. Transient Tie2 activation with AKB-9778 attenuated this trajectory, improving vessel organization, BBB integrity, and memory performance. Our findings show that endothelial instability is a key mechanistic driver of this heterogeneous vascular aging state.
misc TTM+26
Preprint
May. 2026Authors
M. I. Todorov • K. Todorov-Völgy • Minde • S. Kapoor • M. Ali • R. Malik • J. C. Paetzold • J. McGinnis • L. Zhang • A. Nottebrock • L. Liu • M. Simons • H. S. Bhatia • M. K. Georgakis • M. Dichgans • F. Hellal • A. ErtürkLinks
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BibTeXKey: TTM+26