NMDA Reduces Tau Phosphorylation in Rat Hippocampal Slices by Targeting NR2A Receptors, GSK3β, and PKC Activities

Figure 8

Working model of NMDA-induced reduction of Tau phosphorylation. Activation of NR2A-containing receptors appears to initiate Tau phosphorylation through a mechanism involving calcium accumulation and, consequently, GSK3β inactivation via Ser9 phosphorylation by PKC. Through an unknown mechanism, the PKC/GSK3β pathway could selectively reduce the phosphorylation of Ser199-202 residues in the proline-rich domain of Tau. Physiologically, activation of NR2A-containing receptors may reduce Tau phosphorylation which could have an impact on protein localisation and aggregation in neurons. The possibility of a positive feedback loop between PKC activation and stimulation of NMDA receptors cannot be excluded [27]. Accordingly, Jones et al. [28] recently demonstrated that activation of the atypical isoform PKC zeta (PKCζ) is selectively coupled with potentiation of NR2A-containing NMDA receptors.