A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk

Andrew C. Yang (), Ryan T. Vest, Fabian Kern, Davis P. Lee, Maayan Agam, Christina A. Maat, Patricia M. Losada, Michelle B. Chen, Nicholas Schaum, Nathalie Khoury, Angus Toland, Kruti Calcuttawala, Heather Shin, Róbert Pálovics, Andrew Shin, Elizabeth Y. Wang, Jian Luo, David Gate, Walter J. Schulz-Schaeffer, Pauline Chu, Julie A. Siegenthaler, M. Windy McNerney, Andreas Keller and Tony Wyss-Coray ()
Additional contact information
Andrew C. Yang: University of California San Francisco
Ryan T. Vest: Stanford University School of Medicine
Fabian Kern: Stanford University School of Medicine
Davis P. Lee: Stanford University School of Medicine
Maayan Agam: Stanford University School of Medicine
Christina A. Maat: Stanford University School of Medicine
Patricia M. Losada: Stanford University School of Medicine
Michelle B. Chen: University of California San Francisco
Nicholas Schaum: Stanford University School of Medicine
Nathalie Khoury: Stanford University School of Medicine
Angus Toland: Stanford University School of Medicine
Kruti Calcuttawala: Stanford University School of Medicine
Heather Shin: Stanford University School of Medicine
Róbert Pálovics: Stanford University School of Medicine
Andrew Shin: Stanford University School of Medicine
Elizabeth Y. Wang: Icahn School of Medicine at Mount Sinai
Jian Luo: Veterans Administration Palo Alto Healthcare System
David Gate: Stanford University School of Medicine
Walter J. Schulz-Schaeffer: Saarland University Hospital and Medical Faculty of Saarland University
Pauline Chu: Saarland University
Julie A. Siegenthaler: University of Colorado Anschutz Medical Campus
M. Windy McNerney: Stanford University School of Medicine
Andreas Keller: Stanford University School of Medicine
Tony Wyss-Coray: University of California San Francisco

Nature, 2022, vol. 603, issue 7903, 885-892

Abstract: Abstract The human brain vasculature is of great medical importance: its dysfunction causes disability and death1, and the specialized structure it forms—the blood–brain barrier—impedes the treatment of nearly all brain disorders2,3. Yet so far, we have no molecular map of the human brain vasculature. Here we develop vessel isolation and nuclei extraction for sequencing (VINE-seq) to profile the major vascular and perivascular cell types of the human brain through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 9 individuals with Alzheimer’s disease and 8 individuals with no cognitive impairment. We identify brain-region- and species-enriched genes and pathways. We reveal molecular principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In Alzheimer’s disease, we observe selective vulnerability of ECM-maintaining pericytes and gene expression patterns that implicate dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 genes that have been linked to Alzheimer’s disease risk by genome-wide association studies (GWASs) are expressed in the human brain vasculature, and we confirm this by immunostaining. Vascular GWAS genes map to endothelial protein transport, adaptive immune and ECM pathways. Many are microglia-specific in mice, suggesting a partial evolutionary transfer of Alzheimer’s disease risk. Our work uncovers the molecular basis of the human brain vasculature, which will inform our understanding of overall brain health, disease and therapy.

Date: 2022
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DOI: 10.1038/s41586-021-04369-3

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