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

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.

Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease

“…There is overwhelming evidence for cerebrovascular alterations in AD pathology and amyloid-β deposition around leptomeningeal vessels is a hall mark of cerebral amyloid angiopathy, occurring in almost all AD patients (Greenberg et al, 2020). Of interest, recent scRNAseq profiling of human brain vasculature from healthy and AD cerebral cortex showed that perivascular fibroblasts were significantly under-represented in the AD brain single cell data set (Yang et al, 2021; Figure 3B). This is in contrast to large increases in CNS fibroblast numbers after acute CNS injuries and in neuroinflammation, demonstrating a different response of perivascular fibroblasts in AD.…”

Interplay between Brain Pericytes and Endothelial Cells in Dementia

“…32 However, more recently, sequencing has revealed the hippocampus to have fewer pericytes than cortical tissue. 9 In three regions of mouse brain, coverage was approximately 80%, whereas in the spinal cord, pericyte coverage varied from 48% to 68%, depending on location. 79 An additional reason for differences in vessel coverage data is that pericyte coverage appears heterogeneous, dependent on subtype, which relates to vessel diameter.…”

“…46 In addition, a large number of ADrelated genome-wide association study genes are found in vascular cells. 9 Evidence of BBB disruption has been found in postmortem tissue from patients with AD and cSVD. 28,31 In particular, patients with AD and APOE4 have increased deposition of the blood component fibrin(ogen) perivascularly, 31 suggestive of leakage.…”

“…In human tissue, pericytes form two subtypes with enriched gene expression of either transmembrane transporters or extracellular matrix (ECM) regulation genes. 9 In addition, pericyte morphology plays an important role in maintaining BBB integrity because pericytes in the median eminence (ME), where BBB leakage naturally occurs, have a more irregular shape and less prominent nucleus compared with cortical tissue with a functional BBB. 10 A recent article took an in-depth look at pericytes in the mouse cortex and found that, depending on location along the vascular tree, pericytes have different phenotypes.…”

“…11 Despite a morphologic continuum in mice, there appears to be a more distinct difference in gene expression between VSMCs and pericytes in humans. 9 Much of the literature makes no distinctions between pericyte subtypes because of not assessing morphologic differences. Furthermore, platelet-derived growth factor receptor b (PDGFR-b), which is expressed in all pericyte subtypes, 11 is frequently used as a pericyte marker.…”