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

TY - JOUR

T1 - Proteomics of mouse brain endothelium uncovers dysregulation of vesicular transport pathways during aging

AU - Todorov-Völgyi, Katalin

AU - González-Gallego, Judit

AU - Müller, Stephan A

AU - Beaufort, Nathalie

AU - Malik, Rainer

AU - Schifferer, Martina

AU - Todorov, Mihail Ivilinov

AU - Crusius, Dennis

AU - Robinson, Sophie

AU - Schmidt, Andree

AU - Körbelin, Jakob

AU - Bareyre, Florence

AU - Ertürk, Ali

AU - Haass, Christian

AU - Simons, Mikael

AU - Paquet, Dominik

AU - Lichtenthaler, Stefan F

AU - Dichgans, Martin

N1 - © 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2024/4

Y1 - 2024/4

N2 - 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.

AB - 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.

KW - Mice

KW - Animals

KW - Endothelial Cells/metabolism

KW - Proteomics/methods

KW - Brain/metabolism

KW - Endothelium/metabolism

KW - Apolipoproteins E/metabolism

U2 - 10.1038/s43587-024-00598-z

DO - 10.1038/s43587-024-00598-z

M3 - SCORING: Journal article

C2 - 38519806

VL - 4

SP - 595

EP - 612

JO - NATURE AGING

JF - NATURE AGING

SN - 2662-8465

IS - 4

ER -