RT Journal Article
SR Electronic
T1 A human brain vascular atlas reveals diverse cell mediators of Alzheimer’s disease risk
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.04.26.441262
DO 10.1101/2021.04.26.441262
A1 Andrew C. Yang
A1 Ryan T. Vest
A1 Fabian Kern
A1 Davis P. Lee
A1 Christina A. Maat
A1 Patricia M. Losada
A1 Michelle B. Chen
A1 Maayan Agam
A1 Nicholas Schaum
A1 Nathalie Khoury
A1 Kruti Calcuttawala
A1 Róbert Pálovics
A1 Andrew Shin
A1 Elizabeth Y. Wang
A1 Jian Luo
A1 David Gate
A1 Julie A. Siegenthaler
A1 M. Windy McNerney
A1 Andreas Keller
A1 Tony Wyss-Coray
YR 2021
UL http://biorxiv.org/content/early/2021/04/27/2021.04.26.441262.abstract
AB The human brain vasculature is of vast medical importance: its dysfunction causes disability and death, and the specialized structure it forms—the blood-brain barrier—impedes treatment of nearly all brain disorders. Yet, no molecular atlas of the human brain vasculature exists. Here, we develop Vessel Isolation and Nuclei Extraction for Sequencing (VINE-seq) to profile the major human brain vascular and perivascular cell types through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 17 control and Alzheimer’s disease (AD) patients. We identify brain region-enriched pathways and genes divergent between humans and mice, including those involved in disease. We describe the principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum; but discover that many zonation and cell-type markers differ between species. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In AD, we observe a selective vulnerability of ECM-maintaining pericytes and gene expression patterns implicating dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 AD GWAS genes are expressed in the human brain vasculature, confirmed in situ. Vascular GWAS genes map to endothelial protein transport, adaptive immune, and ECM pathways. Many are microglia-specific in mice, suggesting an evolutionary transfer of AD risk to human vascular cells. Our work unravels the molecular basis of the human brain vasculature, informing our understanding of overall brain health, disease, and therapy.Competing Interest StatementThe authors have declared no competing interest.