Isolation and analysis of the brain’s vascular cells increase understanding of the human brain.
We think the reason for this lack of progress is that vascular cells and nuclei are difficult to recover from human post-mortem brain tissue, because the nuclei remain stuck in the basement membrane — the sheet-like extracellular matrix that provides the structure of microvessels. As a result, a molecular map of the human brain vasculature has, to our knowledge, not yet been developed.
Using VINE-seq, we were able to capture 143,793 nuclear transcripts from 15 major cell types in the 2 brain regions . The number of cerebrovascular nuclei we obtained exceeded those of previous studies by several hundred-fold. We found that hippocampal endothelial cells showed higher baseline levels of inflammatory gene expression than did those from the cortex, perhaps explaining why the hippocampal vasculature is more vulnerable to age-related dysfunction.
Although we have shown expression of genes related to Alzheimer’s disease in the brain vasculature, our work has not mechanistically established to what degree these cells and associated genes are involved in the pathogenesis of this disorder. Further research is required to understand the relevant dynamics. And, as with all transcriptional studies, it is impossible to disentangle whether these changes are drivers of disease or a response to it.
Now that we have established the VINE-seq method, we hope that more data sets can be generated with greater sample numbers in various disease and ageing contexts. We also want to investigate the mechanism of action of the various GWAS-prioritized genes associated with Alzheimer’s disease in vascular cells to see whether these cells are sufficient to drive pathology.Expert opinion
This important study is a rich resource of information on the gene expression of blood-vessel-associated cells in the human brain, and will be very valuable to researchers. As the authors describe, therapeutic strategies for Alzheimer’s disease in mouse models have not translated well to therapies in humans, and the substantial differences they describe between the transcriptomes of mice and humans may underlie this, at least in part.
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