The decline of brain endothelial cell (BEC) function, due to aging, is a contributor to neurological disease. BECs lining the inner walls of blood vessels regulate the exchange of molecules across the blood brain barrier—between the circulatory and nervous system.

Previous studies have shown that various functions dependent on BECs, such as the integrity of the blood-brain barrier or the regulation of blood supply to the brain, decline over a lifespan. This dysregulation leads to a dysfunction of the brain vasculature and is therefore a major contributor to medical conditions such as strokes and dementia. However, the molecular changes that underlie this loss of function have remained largely unknown.

“The transcriptome—that is to say, the RNA contained in endothelial cells—has since been quite comprehensively mapped,” says Martin Dichgans, MD, professor at Ludwig Maximilian University (LMU) in Munich, Germany and director of the Institute for Stroke and Dementia Research at University of Munich Hospital, and principal investigator at the SyNergy Cluster of Excellence. “What has been lacking is corresponding data on the complete set of proteins in the cells, the proteome.”

To improve a mechanistic understanding by obtaining more proteomic information, researchers carried out molecular profiling studies to investigate the different components of brain endothelial cells. The team developed a “magnetic-activated cell sorting-based mouse BEC enrichment protocol compatible with proteomics and resolved the profiles of protein abundance changes during aging.”

“The results complement and expand findings from studies on the RNA sequencing of brain endothelial cells during aging,” notes Dichgans. “Our proteomic approach captures processes that are not detected at the RNA level.”

This work is published in Nature Aging in the paper, “Proteomics of mouse brain endothelium uncovers dysregulation of vesicular transport pathways during aging.”

For the study, the team developed a protocol for enriching brain endothelial cells in mice, which makes it possible to resolve age-related changes in the proteome. Using an unsupervised (computer-aided) cluster analysis, the scientists then related these protein dynamics to biological functions.

“Our results show a dysregulation of key molecules involved in the uptake of substances into cells, in receptor recycling, and in the degradation of molecules within specific cellular compartments called lysosomes,” says Dichgans.

More specifically, the work revealed “a segregation of age-related protein dynamics with biological functions, including a downregulation of vesicle-mediated transport.” They found a dysregulation of key regulators of endocytosis and receptor recycling (most prominently Arf6), macropinocytosis and lysosomal degradation.

One of the most striking changes concerned a decrease in proteins involved in vesicle-mediated transport. In addition, the study provides evidence that deficiency of apolipoprotein E, a protein involved in lipid metabolism results in a signature of accelerated endothelial aging.

Overall, the study offers a framework for understanding important endothelial signaling pathways during aging and serves as a data basis for future analyses of brain endothelial function. The researchers are making their data on age-related protein abundance of the mouse endothelium available in a publicly accessible database for further use.

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