A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer’s disease

Stergios Tsartsalis, Hannah Sleven, Nurun Fancy, Frank Wessely, Amy M. Smith, Nanet Willumsen, To Ka Dorcas Cheung, Michal J. Rokicki, Vicky Chau, Eseoghene Ifie, Combiz Khozoie, Olaf Ansorge, Xin Yang, Marion H. Jenkyns, Karen Davey, Aisling McGarry, Robert C. J. Muirhead, Stephanie Debette, Johanna S. Jackson, Axel Montagne, David R. Owen, J. Scott Miners, Seth Love, Caleb Webber, M. Zameel Cader and Paul M. Matthews ()
Additional contact information
Stergios Tsartsalis: Imperial College London
Hannah Sleven: University of Oxford
Nurun Fancy: Imperial College London
Frank Wessely: Cardiff University
Amy M. Smith: Imperial College London
Nanet Willumsen: Imperial College London
To Ka Dorcas Cheung: Imperial College London
Michal J. Rokicki: Cardiff University
Vicky Chau: Imperial College London
Eseoghene Ifie: University of Oxford
Combiz Khozoie: Imperial College London
Olaf Ansorge: University of Oxford
Xin Yang: Imperial College London
Marion H. Jenkyns: Imperial College London
Karen Davey: Imperial College London
Aisling McGarry: Imperial College London
Robert C. J. Muirhead: Imperial College London
Stephanie Debette: UMR 1219
Johanna S. Jackson: Imperial College London
Axel Montagne: University of Edinburgh
David R. Owen: Imperial College London
J. Scott Miners: University of Bristol
Seth Love: University of Bristol
Caleb Webber: Cardiff University
M. Zameel Cader: University of Oxford
Paul M. Matthews: Imperial College London

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Brain perfusion and blood-brain barrier (BBB) integrity are reduced early in Alzheimer’s disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and non-diseased control brains to characterise pathological transcriptional signatures responsible for this. We show that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. Increased β-amyloid is associated with BBB impairment and a dysfunctional angiogenic response related to a failure of increased pro-angiogenic HIF1A to increased VEGFA signalling to EC. This is associated with vascular inflammatory activation, EC senescence and apoptosis. Our genomic dissection of vascular cell risk gene enrichment provides evidence for a role of EC pathology in AD and suggests that reducing vascular inflammatory activation and restoring effective angiogenesis could reduce vascular dysfunction contributing to the genesis or progression of early AD.

Date: 2024
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DOI: 10.1038/s41467-024-46630-z

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