2025-02-26 スタンフォード大学
<関連情報>
- https://news.stanford.edu/stories/2025/02/study-links-the-sugars-on-cell-surfaces-to-brain-resilience
- https://www.nature.com/articles/s41586-025-08589-9
糖鎖の調節異常は老化と疾患における血液脳関門を障害する Glycocalyx dysregulation impairs blood–brain barrier in ageing and disease
Sophia M. Shi,Ryan J. Suh,D. Judy Shon,Francisco J. Garcia,Josephine K. Buff,Micaiah Atkins,Lulin Li,Nannan Lu,Bryan Sun,Jian Luo,Ning-Sum To,Tom H. Cheung,M. Windy McNerney,Myriam Heiman,Carolyn R. Bertozzi & Tony Wyss-Coray
Nature Published:26 February 2025
DOI:https://doi.org/10.1038/s41586-025-08589-9
Abstract
The blood–brain barrier (BBB) is highly specialized to protect the brain from harmful circulating factors in the blood and maintain brain homeostasis. The brain endothelial glycocalyx layer, a carbohydrate-rich meshwork composed primarily of proteoglycans, glycoproteins and glycolipids that coats the BBB lumen, is a key structural component of the BBB. This layer forms the first interface between the blood and brain vasculature, yet little is known about its composition and roles in supporting BBB function in homeostatic and diseased states. Here we find that the brain endothelial glycocalyx is highly dysregulated during ageing and neurodegenerative disease. We identify significant perturbation in an underexplored class of densely O-glycosylated proteins known as mucin-domain glycoproteins. We demonstrate that ageing- and disease-associated aberrations in brain endothelial mucin-domain glycoproteins lead to dysregulated BBB function and, in severe cases, brain haemorrhaging in mice. Finally, we demonstrate that we can improve BBB function and reduce neuroinflammation and cognitive deficits in aged mice by restoring core 1 mucin-type O-glycans to the brain endothelium using adeno-associated viruses. Cumulatively, our findings provide a detailed compositional and structural mapping of the ageing brain endothelial glycocalyx layer and reveal important consequences of ageing- and disease-associated glycocalyx dysregulation on BBB integrity and brain health.
