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

Nat Commun. 2024 Mar 12;15(1):2243. doi: 10.1038/s41467-024-46630-z.

Authors

Stergios Tsartsalis^#^{1

2}, Hannah Sleven^#³, Nurun Fancy^#^{1

4}, Frank Wessely⁵, Amy M Smith^{1

4

6}, Nanet Willumsen^{1

4}, To Ka Dorcas Cheung^{1

4}, Michal J Rokicki⁵, Vicky Chau⁴, Eseoghene Ifie⁷, Combiz Khozoie^{1

4}, Olaf Ansorge⁷, Xin Yang^{1

8}, Marion H Jenkyns¹, Karen Davey^{1

4}, Aisling McGarry^{1

4}, Robert C J Muirhead^{1

4}, Stephanie Debette⁹, Johanna S Jackson^{1

4}, Axel Montagne¹⁰, David R Owen¹, J Scott Miners¹¹, Seth Love¹¹, Caleb Webber⁵, M Zameel Cader³, Paul M Matthews^{12

13

14}

Affiliations

¹ Department of Brain Sciences, Imperial College London, London, UK.
² Department of Psychiatry, University of Geneva, Geneva, Switzerland.
³ Nuffield Department of Clinical Neurosciences, Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, Sherrington Road, University of Oxford, Oxford, UK.
⁴ UK Dementia Research Institute Centre, Imperial College London, London, UK.
⁵ UK Dementia Research Institute Centre, Cardiff University, Cardiff, UK.
⁶ Centre for Brain Research and Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand.
⁷ Neuropathology Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
⁸ St Edmund Hall, University of Oxford, Oxford, UK.
⁹ University of Bordeaux, Inserm, Bordeaux Population Health Research Center, Team ELEANOR, UMR 1219, 33000, Bordeaux, France.
¹⁰ Centre for Clinical Brain Sciences, and UK Dementia Research Institute, University of Edinburgh, Edinburgh, EH16 4SB, UK.
¹¹ Dementia Research Group, University of Bristol, Bristol, UK.
¹² Department of Brain Sciences, Imperial College London, London, UK. p.matthews@imperial.ac.uk.
¹³ UK Dementia Research Institute Centre, Imperial College London, London, UK. p.matthews@imperial.ac.uk.
¹⁴ St Edmund Hall, University of Oxford, Oxford, UK. p.matthews@imperial.ac.uk.

^# Contributed equally.

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.

MeSH terms

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

Substances

Amyloid beta-Peptides