A Single Nuclear Transcriptomic Characterisation of Mechanisms Responsible for Impaired Angiogenesis and Blood-brain Barrier Function in Alzheimer's Disease

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Mar 13

PMID 38472200

Authors

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

Affiliations

Soon will be listed here.

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.

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