Blockade of Lysosomal Acid Ceramidase Induces GluN2B-Dependent Tau Phosphorylation in Rat Hippocampal Slices

Figure 6

Model of Tau phosphorylation during acid ceramidase inhibition. Endogenous accumulation of ceramide is known to be rapidly observed during acid ceramidase inhibition by d-NMAPPD. Here, this inhibitor appears to accentuate NMDA receptor function through a mechanism involving GluN2B receptor phosphorylation at the Tyr1472 epitope. Consequently, calcium might selectively enhance the phosphorylation of Ser262 residues in the microtubule-binding domain of Tau via activation of the CaMKII pathway. Physiologically, acid ceramidase inactivation may induce Tau hyperphosphorylation which could have an impact on protein localization and aggregation in cells and, ultimately, on neuronal survival.