"The Cerebrovascular Glycocalyx in Brain Aging and Neurodegenerative Disease"
The brain vascular lumen is coated by a carbohydrate-rich meshwork of proteoglycans, glycoproteins, and glycolipids known as the brain endothelial glycocalyx layer. This several 100 µm-thick layer is considered the first interface between the blood and brain vasculature, yet very little is known about its composition and roles in supporting blood-brain barrier (BBB) function in homeostatic and diseased states. Using transcriptomic, proteomic, and functional analyses, we reveal that mucin-domain glycoproteins, a class of heavily O-glycosylated proteins, are significantly dysregulated in the aging and diseased brain vasculature. Restoration of mucin-type O-glycosylation in aged mice improves BBB integrity and enhances brain health and function, uncovering a novel neurovascular mechanism of aging. We further investigate the therapeutic potential of vascular glycans through the development of glycocalyx-binding delivery systems, which enable targeted transport of antibodies and other therapeutically relevant cargo across the BBB in vivo. These findings establish a new glycan-mediated route for CNS drug delivery. Collectively, this work identifies the brain endothelial glycocalyx as a critical regulator of BBB function and CNS aging, offering new mechanistic insights and therapeutic strategies for the treatment of neurodegenerative diseases.