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

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Title: A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer’s disease
Authors: Tsartsalis, S
Sleven, H
Fancy, N
Wessely, F
Smith, AM
Willumsen, N
Cheung, TKD
Rokicki, MJ
Chau, V
Ifie, E
Khozoie, C
Ansorge, O
Yang, X
Jenkyns, MH
Davey, K
McGarry, A
Muirhead, RCJ
Debette, S
Jackson, JS
Montagne, A
Owen, DR
Miners, JS
Love, S
Webber, C
Cader, MZ
Matthews, PM
Item Type: Journal Article
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.
Issue Date: 12-Mar-2024
Date of Acceptance: 29-Feb-2024
URI: http://hdl.handle.net/10044/1/111108
DOI: 10.1038/s41467-024-46630-z
ISSN: 2041-1723
Publisher: Nature Portfolio
Journal / Book Title: Nature Communications
Volume: 15
Copyright Statement: © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/.
Publication Status: Published
Article Number: 2243
Online Publication Date: 2024-03-12
Appears in Collections:Faculty of Medicine
Department of Brain Sciences



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