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Todorov-Völgyi, K.* ; González-Gallego, J.* ; Müller, S.A.* ; Beaufort, N.* ; Malik, R.* ; Schifferer, M.* ; Todorov, M.I. ; Crusius, D.* ; Robinson, S.* ; Schmidt, A.* ; Körbelin, J.* ; Bareyre, F.* ; Ertürk, A. ; Haass, C.* ; Simons, M.* ; Paquet, D.* ; Lichtenthaler, S.F.* ; Dichgans, M.*

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

Nature Aging 4, 595-612 (2024)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Proteins; Age; Cells; Apoe; Dysfunction; Expression; Disease; Arf6; Consequences; Hippocampal

ISSN (print) / ISBN 2662-8465

e-ISSN 2662-8465

Journal Nature Aging

Quellenangaben Volume: 4, Issue: 4, Pages: 595-612

Publisher Springer

Publishing Place Campus, 4 Crinan St, London, N1 9xw, England

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute for Tissue Engineering and Regenerative Medicine (ITERM)

Grants Deutsche Forschungsgemeinschaft (German Research Foundation)
ERA-NET Neuron
Leducq Foundation
Vascular Dementia Research Foundation, through the Federal Ministry for Education and Research (BMBF)
Deutsche Forschungsgemeinschaft (DFG), as part of the Munich Cluster for Systems Neurology
European Innovation Council program
European Union's Horizon 2020 Research and Innovation Program SVDs@target
LMUexcellent fund