Ageing disrupts a key sugar-protein layer called the glycocalyx lining brain blood vessels, weakening the blood–brain barrier and increasing brain inflammation and cognitive decline; restoring this layer in mice improves brain health and memory.
February 2025 – Nature
Key takeaways
- Glycocalyx deterioration compromises the brain: Ageing leads to substantial thinning and structural loss of the glycocalyx layer on brain blood vessels, particularly due to reduced mucin-type O-glycosylation. This breakdown weakens the blood–brain barrier, increasing its permeability and allowing neurotoxic molecules to enter the brain, which contributes to heightened inflammation, disrupted brain homeostasis, and cognitive impairments in older individuals
- Mucin-type O-glycans are crucial gatekeepers: Mucin-domain glycoproteins, densely coated with O-glycans, form a critical barrier on brain endothelial cells that stabilises the blood–brain barrier. Age-related downregulation of the enzymes needed to produce these glycans leads to reduced coverage and structural integrity, resulting in barrier leakage and even cerebral haemorrhaging, highlighting their essential role in vascular and brain protection
- Targeted restoration reverses age-related damage: Reinstating mucin-type O-glycosylation in aged mice by overexpressing key glycosylation enzymes led to a significant restoration of the glycocalyx. This intervention improved blood–brain barrier integrity, reduced leakage of harmful blood-derived factors, and mitigated neuroinflammatory responses, presenting a promising therapeutic route for preserving brain health and preventing cognitive decline during ageing
- Brain resilience linked to endothelial health: Enhancing glycocalyx integrity in ageing mice not only improved vascular function but also restored more youthful gene activity in neurons and glial cells. This was accompanied by reduced glial activation and improved performance in memory and learning tasks, reinforcing the idea that brain endothelial health is a powerful driver of cognitive longevity and neurological resilience
Read the article at: Shi, Sophia M., et al. “Glycocalyx Dysregulation Impairs Blood–Brain Barrier in Ageing and Disease.” Nature, vol. 639, 2025, pp. 985–993. https://doi.org/10.1038/s41586-025-08589-9.
