This is a summary of Todorov-Völgyi, K., Gonzalez-Gallego, J. Müller, S.A, Beaufort, N., Malik, R., et al. ‘Proteomics of mouse brain endothelium uncovers dysregulation of vesicular transport pathways during aging.’ which appeared in Nature Aging (2024). https://doi.org/10.1038/s43587-024-00598-z
The challenge
Brain endothelial cells (BECs) are critical components of the blood-brain barrier and safeguard the central nervous system. They line the inner walls of blood vessels that regulate the exchange of molecules between the circulatory and nervous systems. Earlier studies have shown that various functions dependent on these cells, such as the integrity of the blood-brain barrier or the regulation of blood supply to the brain, decline with aging. This leads to a dysfunction of the brain’s vascular system and contributes to medical conditions such as stroke and dementia. The molecular changes underlying this loss of function are unclear. The transcriptome has been mapped, but the proteome – corresponding data on the complete set of proteins in the cells – has not, which is what we set out to do.
Our approach
We developed a mass spectrometry-compatible protocol to characterize the mouse BEC proteome during aging. Using a computer-aided cluster analysis, we related these protein dynamics to biological functions to identify distinct aging patterns.
Our findings
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. One of the most striking changes concerned a decrease in proteins involved in vesicle-mediated transport. In addition, we provide evidence that deficiency of apolipoprotein E (APOE) results in a signature of accelerated endothelial aging. We identified Arf6, a key regulator of endocytosis and receptor recycling, as a candidate factor mediating vesicular transport changes during aging.
The implications
Our study provides a framework for understanding critical endothelial pathways during aging and serves as a resource for analyses of BECs' function in health and disease.
Creating SyNergies
The study, led by Martin Dichgans, is a collaboration of SyNergy investigators, including Martina Schifferer, Florence Bareyre, Ali Ertürk, Christian Haass, Mikael Simons, Dominik Paquet, and Stefan Lichtenthaler. We have made our data publicly available for future studies and collaborations via an interactive website (accessible at https://becaging.de/).
