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 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.
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.
UR - http://www.scopus.com/inward/record.url?scp=85188470836&partnerID=8YFLogxK
U2 - 10.1038/s43587-024-00598-z
DO - 10.1038/s43587-024-00598-z
M3 - Article
AN - SCOPUS:85188470836
SN - 2662-8465
VL - 4
SP - 595
EP - 612
JO - Nature Aging
JF - Nature Aging
IS - 4
ER -