斯坦福大学医学院Tony Wyss-Coray团队报道了糖萼失调在衰老和疾病中损害血脑屏障。相关论文于2025年2月26日发表于国际顶尖学术期刊《自然》杂志上。

在这里，研究组发现脑内皮糖萼在衰老和神经退行性疾病期间高度失调。小组发现了一个未被充分开发的密集O糖基化蛋白（称为粘蛋白结构域糖蛋白）的显著扰动。该研究组证明，脑内皮粘蛋白结构域糖蛋白的衰老和疾病相关畸变导致血脑屏障功能失调，在严重的情况下，小鼠脑出血。最后，该课题组证明，通过将核心1黏液型O-聚糖恢复到脑内皮主题腺相关病毒主题，该课题组可以改善脑血脑屏障功能，减少神经炎症和认知缺陷。总的来说，他们的发现提供了老化脑内皮糖萼层的详细组成和结构图，并揭示了衰老和疾病相关的糖萼失调对血脑屏障完整性和脑健康的重要影响。

据了解，血脑屏障（BBB）是高度特化的，用于保护大脑免受血液中有害循环因子的侵害，并维持大脑稳态。脑内皮糖萼层是一种富含碳水化合物的网状结构，主要由蛋白聚糖、糖蛋白和糖脂组成，覆盖在血脑屏障管腔上，是血脑屏障的关键结构成分。这一层形成了血液和脑血管系统之间的第一个界面，但对其组成和在稳态和病变状态下支持血脑屏障功能的作用知之甚少。

附：英文原文

Title: Glycocalyx dysregulation impairs blood–brain barrier in ageing and disease

Author: 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

Issue&Volume: 2025-02-26

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.

DOI: 10.1038/s41586-025-08589-9

Source: https://www.nature.com/articles/s41586-025-08589-9