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

Author

Listed:
  • Stergios Tsartsalis

    (Imperial College London
    University of Geneva)

  • Hannah Sleven

    (University of Oxford)

  • Nurun Fancy

    (Imperial College London
    Imperial College London)

  • Frank Wessely

    (Cardiff University)

  • Amy M. Smith

    (Imperial College London
    Imperial College London
    University of Auckland)

  • Nanet Willumsen

    (Imperial College London
    Imperial College London)

  • To Ka Dorcas Cheung

    (Imperial College London
    Imperial College London)

  • Michal J. Rokicki

    (Cardiff University)

  • Vicky Chau

    (Imperial College London)

  • Eseoghene Ifie

    (University of Oxford)

  • Combiz Khozoie

    (Imperial College London
    Imperial College London)

  • Olaf Ansorge

    (University of Oxford)

  • Xin Yang

    (Imperial College London
    University of Oxford)

  • Marion H. Jenkyns

    (Imperial College London)

  • Karen Davey

    (Imperial College London
    Imperial College London)

  • Aisling McGarry

    (Imperial College London
    Imperial College London)

  • Robert C. J. Muirhead

    (Imperial College London
    Imperial College London)

  • Stephanie Debette

    (UMR 1219)

  • Johanna S. Jackson

    (Imperial College London
    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
    Imperial College London
    University of Oxford)

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.

Suggested Citation

  • 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 Ansor, 2024. "A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer’s disease," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46630-z
    DOI: 10.1038/s41467-024-46630-z
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