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

View ORCID ProfileAndrew C. Yang, Ryan T. Vest, View ORCID ProfileFabian Kern, Davis P. Lee, Christina A. Maat, Patricia M. Losada, Michelle B. Chen, Maayan Agam, Nicholas Schaum, Nathalie Khoury, Kruti Calcuttawala, Róbert Pálovics, Andrew Shin, Elizabeth Y. Wang, Jian Luo, David Gate, Julie A. Siegenthaler, M. Windy McNerney, Andreas Keller, View ORCID ProfileTony Wyss-Coray
doi: https://doi.org/10.1101/2021.04.26.441262
Andrew C. Yang
1Department of Bioengineering, Stanford University School of Medicine, Stanford, California, USA
2ChEM-H, Stanford University, Stanford, California, USA
3Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA
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  • For correspondence: andcyang@stanford.edu twc@stanford.edu
Ryan T. Vest
3Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA
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Fabian Kern
3Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA
4Chair for Clinical Bioinformatics, Saarland University, 66123 Saarbrucken, SL, Germany
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Davis P. Lee
3Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA
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Christina A. Maat
3Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA
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Patricia M. Losada
3Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA
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Michelle B. Chen
1Department of Bioengineering, Stanford University School of Medicine, Stanford, California, USA
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Maayan Agam
3Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA
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Nicholas Schaum
3Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA
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Nathalie Khoury
3Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA
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Kruti Calcuttawala
3Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA
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Róbert Pálovics
3Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA
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Andrew Shin
3Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA
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Elizabeth Y. Wang
5Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA
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Jian Luo
6Veterans Administration Palo Alto Healthcare System, Palo Alto, California, USA
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David Gate
3Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA
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Julie A. Siegenthaler
7Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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M. Windy McNerney
8Department of Psychiatry, Stanford University School of Medicine, Stanford, California, USA
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Andreas Keller
3Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA
4Chair for Clinical Bioinformatics, Saarland University, 66123 Saarbrucken, SL, Germany
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Tony Wyss-Coray
2ChEM-H, Stanford University, Stanford, California, USA
3Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA
9Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA
10Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, California, USA
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  • For correspondence: andcyang@stanford.edu twc@stanford.edu
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Abstract

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 Statement

The authors have declared no competing interest.

Footnotes

  • https://twc-stanford.shinyapps.io/human_bbb

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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A human brain vascular atlas reveals diverse cell mediators of Alzheimer’s disease risk
Andrew C. Yang, Ryan T. Vest, Fabian Kern, Davis P. Lee, Christina A. Maat, Patricia M. Losada, Michelle B. Chen, Maayan Agam, Nicholas Schaum, Nathalie Khoury, Kruti Calcuttawala, Róbert Pálovics, Andrew Shin, Elizabeth Y. Wang, Jian Luo, David Gate, Julie A. Siegenthaler, M. Windy McNerney, Andreas Keller, Tony Wyss-Coray
bioRxiv 2021.04.26.441262; doi: https://doi.org/10.1101/2021.04.26.441262
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A human brain vascular atlas reveals diverse cell mediators of Alzheimer’s disease risk
Andrew C. Yang, Ryan T. Vest, Fabian Kern, Davis P. Lee, Christina A. Maat, Patricia M. Losada, Michelle B. Chen, Maayan Agam, Nicholas Schaum, Nathalie Khoury, Kruti Calcuttawala, Róbert Pálovics, Andrew Shin, Elizabeth Y. Wang, Jian Luo, David Gate, Julie A. Siegenthaler, M. Windy McNerney, Andreas Keller, Tony Wyss-Coray
bioRxiv 2021.04.26.441262; doi: https://doi.org/10.1101/2021.04.26.441262

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