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 () and Tony Wyss-Coray ()
Additional contact information
Sophia M. Shi: Stanford University
Ryan J. Suh: Stanford University School of Medicine
D. Judy Shon: Stanford University
Francisco J. Garcia: Picower Institute for Learning and Memory
Josephine K. Buff: Stanford University School of Medicine
Micaiah Atkins: Stanford University School of Medicine
Lulin Li: Palo Alto Veterans Institute for Research
Nannan Lu: Stanford University School of Medicine
Bryan Sun: Palo Alto Veterans Institute for Research
Jian Luo: Palo Alto Veterans Institute for Research
Ning-Sum To: Hong Kong Center for Neurodegenerative Diseases
Tom H. Cheung: Hong Kong Center for Neurodegenerative Diseases
M. Windy McNerney: Stanford University School of Medicine
Myriam Heiman: Picower Institute for Learning and Memory
Carolyn R. Bertozzi: Stanford University
Tony Wyss-Coray: Stanford University

Nature, 2025, vol. 639, issue 8056, 985-994

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41586-025-08589-9

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