Cross-Talk Between Tau O-GlcNAcylation and the Formation of the Early Driver of Neurodegeneration (Cis P-Thr231-Pro Tau) in Primary Cortical Neurons.

Tau is a microtubule-associated protein. Hyperphosphorylation of tau at neurotoxic sites, particularly at Thr231 within the Thr231-Pro motif, is a pathological hallmark of Alzheimer's disease (AD) and other tauopathies. Phosphorylated tau at Thr231 exists in two distinct conformations: cis and trans. The Cis pThr231-Pro Tau confomer is neurotoxic and promotes neurodegeneration. Furthermore, tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification, and it has been suggested that O-GlcNAcylation of tau can influence tau phosphorylation. In this study, we utilized Thiamet G, an O-GlcNAcase (OGA) inhibitor, to elevate tau O-GlcNAcylation levels. Our findings demonstrate that treatment of nutrient-deprived primary cortical neurons with this OGA inhibitor increased tau O-GlcNAcylation, inhibited the formation of the neurotoxic Cis p-Tau conformation, and reduced neuronal cell loss. Additionally, we observed that the Trans p-Tau conformation represents a normal conformer under physiological conditions. Collectively, our data support tau O-GlcNAcylation as a promising therapeutic strategy for Alzheimer's disease and other tauopathies.