Glycocalyx dysregulation impairs blood-brain barrier in ageing and disease

• 成果类型: Article
• 署名作者: Shi, Sophia M.; Suh, Ryan J.; Shon, D. Judy; Garcia, Francisco J.; Buff, Josephine K.; Atkins, Micaiah; Li, Lulin; Lu, Nannan; Sun, Bryan; Luo, Jian; To, Ning-Sum; Cheung, Tom H.; Mcnerney, M. Windy; Heiman, Myriam; Bertozzi, Carolyn R.; Wyss-Coray, Tony
• 署名单位: Stanford University; Stanford University; Stanford University; Stanford University; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Stanford University; Hong Kong University of Science & Technology; Stanford University; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA Palo Alto Health Care System; Stanford University; Howard Hughes Medical Institute
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2007
• DOI: 10.1038/s41586-025-08589-9
• 发表日期: 2025-03-27
• 关键词: breakdown

摘要

The blood-brain barrier (BBB) is highly specialized to protect the brain from harmful circulating factors in the blood and maintain brain homeostasis1,2. 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 BBB3,4. 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.