Glycation at the Gate: A Brain Endothelial Glycocalyx Model and Therapeutic Roadmap for Alzheimer's Disease.

While Alzheimer's disease (AD) is primarily considered a disorder of protein aggregation, converging evidence from clinical, neuropathological, and mechanistic studies strongly supports the notion that brain endothelial dysfunction is a primary and early event in AD pathogenesis. Brain endothelial pathways are among the most differentially expressed in human AD brains. Brain endothelial alterations precede amyloid deposition and cognitive deficits in experimental AD models and closely parallel the degree of neuronal loss in human AD brains. Despite growing evidence to support brain endothelial contributions to neurodegeneration, studies examining the potential of the brain endothelium as a druggable target in AD have been scarce. Further, there has been a relative paucity of validated fluid biomarkers that can reliably measure brain endothelial injury in AD, independently of overt vascular disease or disruption to other cerebrovascular constituents. In this perspective, we propose a brain endothelial glycocalyx-centric model of AD in which brain endothelial dysfunction, driven predominantly by non-enzymatic glycation and carbonyl stress, acts as a key upstream regulator of aberrant protein trafficking, blood-brain barrier instability, and dysregulated neuro-immune cascades. Further, recent evidence suggests the presence of direct interactions of the brain endothelium with key pathways involved in neuronal survival and synaptic signaling, highlighting potential direct contributions of brain endothelial disturbances to cognitive impairment. Within this framework, we identify several brain endothelial axes, including reduction in carbonyl stress, improved glycation-dependent signaling, attenuation of advanced glycation end-product (AGE)-mediated toxicity, and enhanced endothelial glycocalyx stability and resilience as potential therapeutic approaches in AD. Modulating brain endothelial glycation has potential as a novel therapeutic strategy in AD which may complement other disease-modifying treatments, particularly in the earliest preclinical stages. In conclusion, this framework positions the brain endothelium as a mechanistic hub linking metabolic stress to aberrant protein aggregation and neurodegeneration in AD with potential therapeutic implications in AD and other neurodegenerative disorders.