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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Brain health depends on brain vascular health. The brain is one of the most highly perfused organs in the body, which is necessary to meet its unique metabolic needs4. Brain vascular dysfunction contributes to stroke1, congenital neurological disorders5 and age-related neurodegenerative disease5,6. The brain vasculature forms a special structure—the blood–brain barrier (BBB)—that mediates selective and haemodynamically responsive movement of molecules between the blood and the brain2,3. Although necessary for optimal neuronal function4, the BBB frustrates the pharmacological treatment of nearly all brain disorders7,8, and extensive efforts are underway to discover targets on the human BBB to enhance drug delivery.
Specialized brain vascular properties arise from a complex community of interacting cell types9,10,11: endothelial cells, adjacent mural smooth muscle cells (SMCs) and pericytes, perivascular immune cells, and surrounding astrocytes that differ across brain regions and vary along an arteriovenous gradient12. Heterogeneity along this gradient produces functionally segmented circulatory, metabolic and permeability properties that are necessary for brain health3,5.
Previous work has profiled the mouse brain vasculature12,13,14,15, but it remains unclear how conserved these findings are in humans. Single-nucleus studies have elucidated the cellula
Specialized brain vascular properties arise from a complex community of interacting cell types9,10,11: endothelial cells, adjacent mural smooth muscle cells (SMCs) and pericytes, perivascular immune cells, and surrounding astrocytes that differ across brain regions and vary along an arteriovenous gradient12. Heterogeneity along this gradient produces functionally segmented circulatory, metabolic and permeability properties that are necessary for brain health3,5.
Previous work has profiled the mouse brain vasculature12,13,14,15, but it remains unclear how conserved these findings are in humans. Single-nucleus studies have elucidated the cellular heterogeneity of the human brain in health and disease16,17,18,19. However, although vascular cell density20,21 (70,000 cells per mm3) approaches total glia density2
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