Mucin-domain glycoproteins are overlooked yet crucial components of the brain endothelial glycocalyx, playing essential roles in maintaining cerebrovascular integrity and function. Dysregulation of these glycoproteins has been implicated in aging and neurodegenerative disease, including Alzheimer’s disease. In this study, we used both enzymatic and genetic techniques to investigate the influence of mucin-domain glycoproteins on cerebrovascular biology.