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

Tsartsalis, Stergios, Sleven, Hannah, Fancy, Nurun, Wessely, Frank, Smith, Amy M., Willumsen, Nanet, Cheung, To Ka Dorcas, Rokicki, Michal J., Chau, Vicky, Ifie, Eseoghene, Khozoie, Combiz, Ansorge, Olaf, Yang, Xin, Jenkyns, Marion H., Davey, Karen, McGarry, Aisling, Muirhead, Robert C. J., Debette, Stephanie, Jackson, Johanna S., Montagne, Axel, Owen, David R., Miners, J. Scott, Love, Seth, Webber, Caleb ORCID: https://orcid.org/0000-0001-8063-7674, Cader, M. Zameel and Matthews, Paul M. 2024. A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer’s disease. Nature Communications 15 , 2243. 10.1038/s41467-024-46630-z

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Nature Research
Date of First Compliant Deposit:	14 March 2024
Date of Acceptance:	29 February 2024
Last Modified:	11 Jun 2024 15:03
URI:	https://orca.cardiff.ac.uk/id/eprint/167247

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