Single Cell: Brain Vasculature In Alzheimer's Disease

Single-cell multi-region dissection of brain vasculature in Alzheimer’s Disease

Cerebrovascular breakdown occurs early in Alzheimer’s Disease (AD), but its cell-type-specific molecular basis remains uncharacterized. Here, we characterize single-cell transcriptomic differences in human cerebrovasculature across 220 AD and 208 control individuals and across 6 brain regions. We annotate 22,514 cerebrovascular cells in 11 subtypes of endothelial, pericyte, smooth muscle, pervascular fibroblast, and ependymal cells, and how they differ in abundance and gene expression between brain regions. We identify 2,676 AD-differential genes, including lower expression of PDGFRB in pericytes, and ABCB1 and ATP10A in endothelial cells. These AD-differential genes reveal common upstream regulators, including MECOM, EP300, and KLF4, whose targeting may help restore vasculature function. We find coordinated vasculature-glial-neuronal co-expressed gene modules supported by ligand-receptor pairs, involved in axon growth/degeneration and neurogenesis, suggesting mechanistic mediators of neurovascular unit dysregulation in AD. Integration with AD genetics reveals 125 AD-differential genes directly linked to AD-associated genetic variants (through vasculature-specific eQTLs, Hi-C, and correlation-based evidence), 559 targeted by AD-associated regulators, and 661 targeted by AD-associated ligand-receptor signaling. Lastly, we show that APOE4-genotype associated differences are significantly enriched among AD-associated genes in capillary and venule endothelial cells, and subsets of pericytes and fibroblasts, which underlie the vascular dysregulation in APOE4-associated cognitive decline. Overall, our multi-region molecular atlas of differential human cerebrovasculature genes and pathways in AD can help guide early-stage AD therapeutics.

figure1

Figure 1 Brain vasculature characterization across six brain regions

 

 

Cell information vs gene expression on reduced dimensions

In this tab, users can visualise both cell information and gene expression side-by-side on low-dimensional representions.

Dimension Reduction

Cell information

Download PDF Download PNG

Cell numbers / statistics

Gene expression

Download PDF Download PNG

Cell information vs cell information on dimension reduction

In this tab, users can visualise two cell informations side-by-side on low-dimensional representions.

Dimension Reduction

Cell information 1

Download PDF Download PNG

Cell information 2

Download PDF Download PNG

Gene expression vs gene expression on dimension reduction

In this tab, users can visualise two gene expressions side-by-side on low-dimensional representions.

Dimension Reduction

Gene expression 1

Download PDF Download PNG

Gene expression 2

Download PDF Download PNG

Coexpression of two genes on reduced dimensions

In this tab, users can visualise the coexpression of two genes on low-dimensional representions.

Dimension Reduction

Gene Expression

Download PDF Download PNG

Cell information / gene expression violin plot / box plot

In this tab, users can visualise the gene expression or continuous cell information (e.g. Number of UMIs / module score) across groups of cells (e.g. libary / clusters).



Download PDF Download PNG

Proportion / cell numbers across different cell information

In this tab, users can visualise the composition of single cells based on one discrete cell information across another discrete cell information. Usage examples include the library or cellcycle composition across clusters.



Download PDF Download PNG

Gene expression bubbleplot / heatmap

In this tab, users can visualise the gene expression patterns of multiple genes grouped by categorical cell information (e.g. library / cluster).
The normalised expression are averaged, log-transformed and then plotted.




Download PDF Download PNG






Cell information / gene expression violin plot


Loading...










Differentially Expressed Genes

Download Full Table (TSV)

Differentially Expressed Target Genes





About: