Enzymatic glycosylation as a potential molecular link between Alzheimer's disease and glaucoma.

Alzheimer's disease (AD) and glaucoma are prevalent age-related neurodegenerative disorders affecting the brain and the eye, respectively. Despite their distinct clinical manifestations, both conditions share convergent pathological features, including neuronal loss, neuroinflammation, and metabolic stress, suggesting common upstream regulatory mechanisms. Protein glycosylation, a fundamental post-translational modification, has emerged as a key modulator of neuronal survival, protein aggregation, and inflammatory signaling in neurodegenerative diseases. In this review, we summarize recent advances in enzymatic glycosylation that are mechanistically relevant to both AD and glaucoma, with particular emphasis on N-linked glycosylation (N-glycosylation) and O-linked β-N-acetylglucosaminylation (O-GlcNAcylation). We focus on key enzymes, including O-GlcNAc transferase (OGT), O-GlcNAcase (OGA), and N-acetylglucosaminyltransferase III (GnT-III), and describe their roles in regulating neuronal viability, microglial activation, trabecular meshwork function, and retinal ganglion cell (RGC) survival. Integrating evidence from cerebral and ocular systems, we propose two glycosylation-dependent regulatory axes: the OGT/OGA-O-GlcNAc axis as an upstream metabolic and stress sensor, and the GnT-III-bisecting GlcNAc-intercellular adhesion molecule-1 (ICAM-1) axis as a downstream modulator of neuroinflammatory cell-cell interactions. We discuss the potential of glycosylation signatures as biomarkers in cerebrospinal fluid, plasma, and aqueous humor, and the feasibility of enzyme-targeted modulation as a therapeutic strategy. Collectively, this enzyme-centered framework provides a conceptual and regulatory perspective on potential links between AD and glaucoma, highlighting opportunities for translational research while acknowledging current evidence gaps that warrant further investigation.