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

Abstract

The molecular mechanisms that regulate Tau phosphorylation are complex and currently incompletely understood. In the present study, pharmacological inhibitors were deployed to investigate potential processes by which the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors modulates Tau phosphorylation in rat hippocampal slices. Our results demonstrated that Tau phosphorylation at Ser199-202 residues was decreased in NMDA-treated hippocampal slices, an effect that was not reproduced at Ser262 and Ser404 epitopes. NMDA-induced reduction of Tau phosphorylation at Ser199-202 was further promoted when NR2A-containing receptors were pharmacologically isolated and were completely abrogated by the NR2A receptor antagonist NVP-AAM077. Compared with nontreated slices, we observed that NMDA receptor activation was reflected in high Ser9 and low Tyr216 phosphorylation of glycogen synthase kinase-3 beta (GSK3β), suggesting that NMDA receptor activation might diminish Tau phosphorylation via a pathway involving GSK3β inhibition. Accordingly, we found that GSK3β inactivation by a protein kinase C- (PKC-) dependent mechanism is involved in the NMDA-induced reduction of Tau phosphorylation at Ser199-202 epitopes. Taken together, these data indicate that NR2A receptor activation may be important in limiting Tau phosphorylation by a PKC/GSK3β pathway and strengthen the idea that these receptors might act as an important molecular device counteracting neuronal cell death mechanisms in various pathological conditions.

Conventional protein kinase C in the brain: 40 years later

“…Second, PKC has been implicated in tau phosphorylation indirectly through its ability to phosphorylate and inactivate glycogen synthase kinase-3β (GSK-3β), thereby reducing tau phosphorylation catalyzed by this kinase [68]. PKC has also been linked to N-methyl-d-aspartate receptor (NMDAR)-mediated reduction in tau phosphorylation [69]. Overall, PKC's regulation of cytoskeleton dynamics in the brain plays a critical role not only in synapse formation and maintenance, but also in the functions of non-neuronal cells such as endothelial and glial cells [49].…”

Common Mechanisms of Alzheimer's Disease and Ischemic Stroke: The Role of Protein Kinase C in the Progression of Age-Related Neurodegeneration

“…Although the toxic effects of Aβ are widely known, the study into the evolutionary benefit of Aβ as an antioxidant is in its infancy [127]. PKC isoforms also serve as potent regulators of tau phosphorylation at serine 199–202 [9]. Importantly, PKCα regulates tau binding to tubulin within axons.…”

“…PKCγ also contributes to the preservation of synaptic plasticity [8]. Besides the role that PKC isoforms play in memory formation, they also have important functions as tau kinases [9]. In particular, age-related changes in PKC translocation have been linked to tau hyperphosphorylation and the phosphorylation of glycogen synthase kinase 3β (p-GSK3β) [10].…”

Regulation of GSK-3 Activity as A Shared Mechanism in Psychiatric Disorders

“…It has been reported that GSK-3β activity is increased in response to phencyclidine, a NMDA receptor antagonist, in rat hippocampus, striatum and frontal cortex 97 . It was also shown that administration of NMDA resulted in increased serine phosphorylation of GSK-3β in rats 98 . A limited number of studies have indicated that NMDA receptor stimulation enhanced GSK-3β phosphorylation whereas its blockade increased GSK-3β activity.…”