TY - JOUR
T1 - A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk
AU - Yang, Andrew C.
AU - Vest, Ryan T.
AU - Kern, Fabian
AU - Lee, Davis P.
AU - Agam, Maayan
AU - Maat, Christina A.
AU - Losada, Patricia M.
AU - Chen, Michelle B.
AU - Schaum, Nicholas
AU - Khoury, Nathalie
AU - Toland, Angus
AU - Calcuttawala, Kruti
AU - Shin, Heather
AU - Pálovics, Róbert
AU - Shin, Andrew
AU - Wang, Elizabeth Y.
AU - Luo, Jian
AU - Gate, David
AU - Schulz-Schaeffer, Walter J.
AU - Chu, Pauline
AU - Siegenthaler, Julie A.
AU - McNerney, M. Windy
AU - Keller, Andreas
AU - Wyss-Coray, Tony
N1 - Funding Information:
We thank T. Iram, E. Tapp, N. Lu, M. Haney, O. Hahn, M. J. Estrada, S. M. Shi and other members of the Wyss-Coray laboratory for feedback and support; H. Mathys, D. A. Bennett and participants in the CSHL BBB 2021 meeting for advice; and H. Zhang and K. Dickey for laboratory management. This work was funded by the NOMIS Foundation (T.W.-C.), the National Institute on Aging (T32-AG0047126 to A.C.Y. and 1RF1AG059694 to T.W.-C), Nan Fung Life Sciences (T.W.-C.), the Bertarelli Brain Rejuvenation Sequencing Cluster (an initiative of the Stanford Wu Tsai Neurosciences Institute) and the Stanford Alzheimer’s Disease Research Center (P30 AG066515). This work was supported by a grant from the Simons Foundation Award (811253TWC). A.C.Y. was supported by a Siebel Scholarship. F.K. and A.K. are part of the CORSAAR study supported by the State of Saarland, the Saarland University and the Rolf M. Schwiete Stiftung. This study was supported by the AHA–Allen Initiative in Brain Health and Cognitive Impairment (19PABHI34580007). The statements in this work are solely the responsibility of the authors and do not necessarily represent the views of the American Heart Association (AHA) or the Paul G. Allen Frontiers Group. Graphics were created with BioRender.com.
Funding Information:
We thank T. Iram, E. Tapp, N. Lu, M. Haney, O. Hahn, M. J. Estrada, S. M. Shi and other members of the Wyss-Coray laboratory for feedback and support; H. Mathys, D. A. Bennett and participants in the CSHL BBB 2021 meeting for advice; and H. Zhang and K. Dickey for laboratory management. This work was funded by the NOMIS Foundation (T.W.-C.), the National Institute on Aging (T32-AG0047126 to A.C.Y. and 1RF1AG059694 to T.W.-C), Nan Fung Life Sciences (T.W.-C.), the Bertarelli Brain Rejuvenation Sequencing Cluster (an initiative of the Stanford Wu Tsai Neurosciences Institute) and the Stanford Alzheimer?s Disease Research Center (P30 AG066515). This work was supported by a grant from the Simons Foundation Award (811253TWC). A.C.Y. was supported by a Siebel Scholarship. F.K. and A.K. are part of the CORSAAR study supported by the State of Saarland, the Saarland University and the Rolf M. Schwiete Stiftung. This study was supported by the AHA?Allen Initiative in Brain Health and Cognitive Impairment (19PABHI34580007). The statements in this work are solely the responsibility of the authors and do not necessarily represent the views of the American Heart Association (AHA) or the Paul G. Allen Frontiers Group. Graphics were created with BioRender.com.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/3/31
Y1 - 2022/3/31
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85124754414&partnerID=8YFLogxK
U2 - 10.1038/s41586-021-04369-3
DO - 10.1038/s41586-021-04369-3
M3 - Article
C2 - 35165441
AN - SCOPUS:85124754414
SN - 0028-0836
VL - 603
SP - 885
EP - 892
JO - Nature
JF - Nature
IS - 7903
ER -