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

Autor: Todorov-Völgyi K; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany. katalin.voelgyi@med.uni-muenchen.de., González-Gallego J; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.; Graduate School of Systemic Neuroscience (GSN), University Hospital, LMU Munich, Munich, Germany., Müller SA; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany.; Neuroproteomics, School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany., Beaufort N; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany., Malik R; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany., Schifferer M; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany., Todorov MI; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.; Institute for Tissue Engineering and Regenerative Medicine (iTERM), Helmholtz Zentrum München, Neuherberg, Germany., Crusius D; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany., Robinson S; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.; Graduate School of Systemic Neuroscience (GSN), University Hospital, LMU Munich, Munich, Germany.; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany., Schmidt A; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany.; Neuroproteomics, School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany., Körbelin J; Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Bareyre F; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.; Institute of Clinical Neuroimmunology, University Hospital, LMU Munich, Munich, Germany.; Biomedical Center Munich (BMC), Faculty of Medicine, LMU Munich, Planegg-Martinsried, Germany., Ertürk A; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.; Institute for Tissue Engineering and Regenerative Medicine (iTERM), Helmholtz Zentrum München, Neuherberg, Germany., Haass C; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.; Division of Metabolic Biochemistry, Biomedical Center Munich (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany., Simons M; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany., Paquet D; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany., Lichtenthaler SF; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany.; Neuroproteomics, School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany., Dichgans M; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany. martin.dichgans@med.uni-muenchen.de.; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany. martin.dichgans@med.uni-muenchen.de.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. martin.dichgans@med.uni-muenchen.de.
Jazyk: angličtina
Zdroj: Nature aging [Nat Aging] 2024 Apr; Vol. 4 (4), pp. 595-612. Date of Electronic Publication: 2024 Mar 22.
DOI: 10.1038/s43587-024-00598-z
Abstrakt: 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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