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A human brain vascular atlas reveals diverse mediators of Alzheimer's risk.
Yang, Andrew C; Vest, Ryan T; Kern, Fabian; Lee, Davis P; Agam, Maayan; Maat, Christina A; Losada, Patricia M; Chen, Michelle B; Schaum, Nicholas; Khoury, Nathalie; Toland, Angus; Calcuttawala, Kruti; Shin, Heather; Pálovics, Róbert; Shin, Andrew; Wang, Elizabeth Y; Luo, Jian; Gate, David; Schulz-Schaeffer, Walter J; Chu, Pauline; Siegenthaler, Julie A; McNerney, M Windy; Keller, Andreas; Wyss-Coray, Tony.
Affiliation
  • Yang AC; Department of Anatomy, University of California San Francisco, San Francisco, CA, USA. andrew.yang@ucsf.edu.
  • Vest RT; Bakar Aging Research Institute, University of California San Francisco, San Francisco, CA, USA. andrew.yang@ucsf.edu.
  • Kern F; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. andrew.yang@ucsf.edu.
  • Lee DP; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Agam M; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Maat CA; Chair for Clinical Bioinformatics, Saarland University, Saarbrücken, Germany.
  • Losada PM; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Chen MB; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Schaum N; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Khoury N; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Toland A; Department of Anatomy, University of California San Francisco, San Francisco, CA, USA.
  • Calcuttawala K; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Shin H; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Pálovics R; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • Shin A; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Wang EY; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Luo J; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Gate D; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Schulz-Schaeffer WJ; Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Chu P; Veterans Administration Palo Alto Healthcare System, Palo Alto, CA, USA.
  • Siegenthaler JA; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • McNerney MW; Institute for Neuropathology, Saarland University Hospital and Medical Faculty of Saarland University, Homburg, Germany.
  • Keller A; Chair for Clinical Bioinformatics, Saarland University, Saarbrücken, Germany.
  • Wyss-Coray T; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Nature ; 603(7903): 885-892, 2022 03.
Article in En | MEDLINE | ID: mdl-35165441
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain / Disease Susceptibility / Alzheimer Disease Type of study: Etiology_studies / Risk_factors_studies Limits: Animals / Humans Language: En Journal: Nature Year: 2022 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain / Disease Susceptibility / Alzheimer Disease Type of study: Etiology_studies / Risk_factors_studies Limits: Animals / Humans Language: En Journal: Nature Year: 2022 Type: Article Affiliation country: United States