Acute treatment of rTg4510 mice with an O-GlcNAcase inhibitor transiently reduced tau phosphorylation at epitopes implicated in tau pathology. More importantly, long-term inhibitor treatment strongly increased tau O-GlcNAcylation, reduced the number of dystrophic neurons, and protected against the formation of pathological tau species without altering the phosphorylation of non-pathological tau.
Hence, LTD-inducing NMDA receptor activation leads to an increase in tau phosphorylation at sites PHF-1, AT180, as well as AT8 and to a reduction at AT100.
This result is supported by recent studies showing that the interaction between Fyn and tau is regulated through tau phosphorylation at the AT8 site, increasing tau-Fyn interaction by 42-fold after tau is phosphorylated or bearing a phosphomimetic mutation at the AT8 site (63). In our experiments, tau phosphorylation at AT8 is strongly up-regulated through the activation of NMDA receptors (Fig. 3), suggesting that NMDA receptor activation could massively enhance the interaction between tau and Fyn.
This indicates that O-GlcNAcylation prevents the aggregation of tau in a manner that does not affect its normal phosphorylation state.
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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.