The blood-brain barrier surrounds blood vessels passing through the brain and tightly controls which molecules are allowed to pass. It separates the metabolism of the brain from that of the rest of the body. With age, the blood-brain barrier becomes dysfunctional, allowing unwanted cells and molecules to leak into the brain, where they contribute to the chronic inflammation of brain tissue. Researchers here focus on the structure of one specific thin layer of the blood-brain barrier, note that it becomes dysregulated with age, and find a way to improve its function via gene therapy.
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 overexpressing two age-downregulated mucin-type O-glycan biosynthetic enzymes, C1GALT1 and B3GNT3.
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.
Link: https://doi.org/10.1038/s41586-025-08589-9
View the full article at FightAging
