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; Paul M Matthews

doi:10.1038/s41467-024-46630-z

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 MontagneDavid R Owen, J Scott Miners, Seth Love, Caleb Webber, M Zameel Cader, Paul M Matthews^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

7 Citations (Scopus)

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.

Original language	English
Article number	2243
Number of pages	19
Journal	Nature Communications
Volume	15
Issue number	1
Early online date	12 Mar 2024
DOIs	https://doi.org/10.1038/s41467-024-46630-z
Publication status	E-pub ahead of print - 12 Mar 2024

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Publisher Copyright:
© The Author(s) 2024.

Keywords

Humans
Alzheimer Disease/metabolism
Blood-Brain Barrier/metabolism
Endothelial Cells/metabolism
Angiogenesis
Brain/metabolism
Amyloid beta-Peptides/metabolism
Gene Expression Profiling

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Tsartsalis, S., Sleven, H., Fancy, N., Wessely, F., Smith, A. M., Willumsen, N., Cheung, T. K. D., Rokicki, M. J., Chau, V., Ifie, E., Khozoie, C., Ansorge, O., Yang, X., Jenkyns, M. H., Davey, K., McGarry, A., Muirhead, R. C. J., Debette, S., Jackson, J. S., ... Matthews, P. 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(1), Article 2243. Advance online publication. https://doi.org/10.1038/s41467-024-46630-z

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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",

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.",

keywords = "Humans, Alzheimer Disease/metabolism, Blood-Brain Barrier/metabolism, Endothelial Cells/metabolism, Angiogenesis, Brain/metabolism, Amyloid beta-Peptides/metabolism, Gene Expression Profiling",

author = "Stergios Tsartsalis and Hannah Sleven and Nurun Fancy and Frank Wessely and Smith, {Amy M} and Nanet Willumsen and Cheung, {To Ka Dorcas} and Rokicki, {Michal J} and Vicky Chau and Eseoghene Ifie and Combiz Khozoie and Olaf Ansorge and Xin Yang and Jenkyns, {Marion H} and Karen Davey and Aisling McGarry and Muirhead, {Robert C J} and Stephanie Debette and Jackson, {Johanna S} and Axel Montagne and Owen, {David R} and Miners, {J Scott} and Seth Love and Caleb Webber and Cader, {M Zameel} and Matthews, {Paul M}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = mar,

day = "12",

doi = "10.1038/s41467-024-46630-z",

language = "English",

volume = "15",

journal = "Nature Communications",

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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 2024, 'A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer's disease', Nature Communications, vol. 15, no. 1, 2243. https://doi.org/10.1038/s41467-024-46630-z

TY - JOUR

T1 - A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer's disease

AU - Tsartsalis, Stergios

AU - Sleven, Hannah

AU - Fancy, Nurun

AU - Wessely, Frank

AU - Smith, Amy M

AU - Willumsen, Nanet

AU - Cheung, To Ka Dorcas

AU - Rokicki, Michal J

AU - Chau, Vicky

AU - Ifie, Eseoghene

AU - Khozoie, Combiz

AU - Ansorge, Olaf

AU - Yang, Xin

AU - Jenkyns, Marion H

AU - Davey, Karen

AU - McGarry, Aisling

AU - Muirhead, Robert C J

AU - Debette, Stephanie

AU - Jackson, Johanna S

AU - Montagne, Axel

AU - Owen, David R

AU - Miners, J Scott

AU - Love, Seth

AU - Webber, Caleb

AU - Cader, M Zameel

AU - Matthews, Paul M

PY - 2024/3/12

Y1 - 2024/3/12

N2 - 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.

AB - 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.

KW - Humans

KW - Alzheimer Disease/metabolism

KW - Blood-Brain Barrier/metabolism

KW - Endothelial Cells/metabolism

KW - Angiogenesis

KW - Brain/metabolism

KW - Amyloid beta-Peptides/metabolism

KW - Gene Expression Profiling

U2 - 10.1038/s41467-024-46630-z

DO - 10.1038/s41467-024-46630-z

M3 - Article (Academic Journal)

C2 - 38472200

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2243

ER -

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

Abstract

Bibliographical note

Keywords

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