Role of O-GlcNAcylation in Alzheimer's disease: Insights and perspectives

O-GlcNAcylation is a critical post-translational modification involving the addition of N-acetylglucosamine to serine/threonine residues on proteins, significantly influencing their function and stability. In Alzheimer's disease (AD), the modification of the tau protein by O-GlcNAcylation is crucial to its pathophysiology. Tau, which is essential for neuronal microtubule stability, has 80 potential Ser/Thr residues for O-GlcNAcylation. This modification is regulated by O-GlcNAc transferase (OGT), which adds O-GlcNAc groups, and O-β-N-acetyl-d-glucosaminidase (O-GlcNAcase or OGA), which removes them. O-GlcNAcylation competes with phosphorylation—a key factor in tau pathology—by directly occupying phosphorylation sites or glycosylating adjacent residues, thus potentially inhibiting tau hyperphosphorylation and aggregation. The novelty of this approach lies in targeting OGA with inhibitors to increase overall O-GlcNAcylation levels of tau and other proteins, potentially reducing hyperphosphorylation and aggregation associated with AD progression. By inhibiting OGA, these agents can elevate O-GlcNAcylation, offering a protective mechanism against tauopathies and other neurodegenerative changes in AD. This strategy highlights the innovative potential of OGA inhibitors as therapeutic agents, suggesting they could modify disease progression and improve clinical outcomes in AD patients. The development and application of OGA inhibitors thus represent a groundbreaking direction for future therapeutic strategies in combating Alzheimer's disease.