Proteomics of mouse brain endothelium uncovers dysregulation of vesicular transport pathways during aging

Katalin Todorov-Völgyi, Judit González-Gallego, Stephan A. Müller, Nathalie Beaufort, Rainer Malik, Martina Schifferer, Mihail Ivilinov Todorov, Dennis Crusius, Sophie Robinson, Andree Schmidt, Jakob Körbelin, Florence Bareyre, Ali Ertürk, Christian Haass, Mikael Simons, Dominik Paquet, Stefan F. Lichtenthaler, Martin Dichgans

Research output: Contribution to journalArticlepeer-review

Abstract

Age-related decline in brain endothelial cell (BEC) function contributes critically to neurological disease. Comprehensive atlases of the BEC transcriptome have become available, but results from proteomic profiling are lacking. To gain insights into endothelial pathways affected by aging, we developed a magnetic-activated cell sorting-based mouse BEC enrichment protocol compatible with proteomics and resolved the profiles of protein abundance changes during aging. Unsupervised cluster analysis revealed a segregation of age-related protein dynamics with biological functions, including a downregulation of vesicle-mediated transport. We found a dysregulation of key regulators of endocytosis and receptor recycling (most prominently Arf6), macropinocytosis and lysosomal degradation. In gene deletion and overexpression experiments, Arf6 affected endocytosis pathways in endothelial cells. Our approach uncovered changes not picked up by transcriptomic studies, such as accumulation of vesicle cargo and receptor ligands, including Apoe. Proteomic analysis of BECs from Apoe-deficient mice revealed a signature of accelerated aging. Our findings provide a resource for analysing BEC function during aging.

Original languageEnglish
Pages (from-to)595-612
Number of pages18
JournalNature Aging
Volume4
Issue number4
DOIs
StatePublished - Apr 2024
Externally publishedYes

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