老化する脳:タンパク質マッピングが新たな知見をもたらす(The aging brain: protein mapping furnishes new insights)

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2024-03-22 ミュンヘン大学(LMU)

脳の神経細胞が適切に働くためには、中枢神経系が厳密に調整された環境を必要とする。これは血液脳関門によって維持され、脳内皮細胞が血管内壁にあって血液と神経系の分子の交換を調節する。しかし、これらの細胞の機能が低下すると、脳の血管機能が障害され、脳卒中や認知症などの疾患が引き起こされる。これらの機能喪失の分子メカニズムは未解明だったが、最新の研究では、脳内皮細胞のタンパク質組成の年齢関連の変化が明らかにされ、重要な情報が提供された。

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マウス脳内皮のプロテオミクスから、加齢に伴う小胞輸送経路の調節異常が明らかになる 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
Nature Aging  Published22 March 2024
DOIhttps://doi.org/10.1038/s43587-024-00598-z

老化する脳:タンパク質マッピングが新たな知見をもたらす(The aging brain: protein mapping furnishes new insights)

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.

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