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 ChuJulie A. Siegenthaler, M. Windy McNerney, Andreas Keller, Tony Wyss-Coray

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)885-892
Number of pages8
JournalNature
Volume603
Issue number7903
DOIs
StatePublished - Mar 31 2022
Externally publishedYes

ASJC Scopus subject areas

  • General

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