This Stanford study reveals that the brain endothelial glycocalyx plays a key role in protecting the brain and that its degradation may be linked to aging and neurodegenerative diseases. More importantly, it suggests that restoring this layer may be a promising strategy for maintaining the integrity of the blood-brain barrier and combating brain diseases associated with aging.
The human brain is a very sensitive organ and needs to be protected from harmful substances that circulate in the blood. To do this, it relies on the blood-brain barrier (BBB), which acts as an extremely selective filter.
This barrier prevents toxins and inflammatory agents from reaching the brain, while allowing essential nutrients to enter.
This protection is possible thanks to a special structure of the cells that line the brain's blood vessels: they have very tight junctions between them, a highly controlled transport of substances and a layer of carbohydrates called the glycocalyx, which covers their surface.
The brain endothelial glycocalyx is a complex network of molecules that acts as an extra shield for the blood-brain barrier. It helps regulate processes such as the exchange of substances between the blood and the brain, communication between cells, and even the way blood vessels behave.
However, despite its importance, we still know little about its composition and its exact role in protecting the brain.
Diagram of the blood-brain barrier and the brain’s endothelial glycocalyx layer
As we age, the blood-brain barrier can become less effective, allowing harmful substances to enter the brain. This can contribute to diseases such as Alzheimer’s and other neurodegenerative conditions.
To better understand this change, researchers analyzed the glycocalyx in young (3-month-old) and old (21-month-old) mice using electron microscopy, an advanced type of imaging.
The results showed that in the older mice, the glycocalyx was significantly thinner and less dense than in the young mice.
b) Cortical capillaries stained with lanthanum nitrate from young (3 months) and aged (21 months) mice. c) Quantification of the thickness of the luminal endothelial glycocalyx. d) Quantification of the area of the luminal endothelial glycocalyx in mice.
In addition, by examining the genetic activity of the cells of the blood-brain barrier, scientists noticed that the production of certain glycocalyx molecules was altered in aging.
In particular, there was a reduction in the production of mucin-like glycoproteins, a group of carbohydrate-rich molecules that are essential for the structure and function of the glycocalyx.
The decrease in these glycoproteins can weaken the blood-brain barrier, making it more permeable to harmful substances. This was confirmed in experiments with aged mice, in which scientists observed increased brain inflammation and a higher risk of hemorrhage.
Furthermore, studies comparing brain tissue from people with Alzheimer's have shown that dysregulation of the glycocalyx is a common problem in both normal aging and neurodegenerative diseases.
Researchers tested an innovative treatment in elderly mice, using a gene therapy based on modified viruses (adeno-associated viruses) to restore the production of mucin-like glycoproteins.
Glycocalyx restoration with modified virus (C1GALT1, magenta), demonstrating how the technique can be an effective therapeutic approach to restore blood-brain barrier function in conditions of diseases associated with aging.
The results were promising: the blood-brain barrier was strengthened, there was a reduction in brain inflammation and an improvement in cognitive function in the treated mice.
The study reveals that the brain endothelial glycocalyx plays a fundamental role in protecting the brain and that its degradation may be linked to aging and neurodegenerative diseases.
Schematic of blood-brain barrier dysfunction during aging and neurodegenerative diseases, highlighting new findings from this paper. The endothelial layer of the brain glycocalyx degenerates with aging, thus contributing to dysregulated blood-brain barrier function.
More importantly, it suggests that restoring this layer may be a promising strategy for maintaining blood-brain barrier integrity and combating age-associated brain diseases.
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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
Nature. 26 February 2025
DOI: 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 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.
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