Objective: Memantine is a moderate affinity uncompetitive NMDA receptor antagonist used for many years to treat dementias. The activity of protein phosphatase 2A (PP-2A), a major regulator of tau phosphorylation, is compromised in Alzheimer’s disease (AD) and believed to be a cause of abnormal tau hyperphosphorylation and consequent neurofibrillary degeneration. We sought to learn whether the therapeutic effect of memantine could involve inhibition of neurofibrillary degeneration.
Design/Methods: We investigated the effect of memantine on okadaic acid-induced decrease of PP-2A activity, kinase activities affected by PP-2A, and tau phosphorylation in adult rat hippocampal slices in culture. Long-term hippocampal culture slices were prepared from month-old Wistar rats using the interface method. Treatments were carried out by adding drug to the culture medium.
Results: Treatment with 100 nM okadaic acid for 24 hours resulted in ~40% inhibition of PP-2A, ~70% increase in CaMKII activity, and ~2-fold increase in tau phosphorylation at Ser262. Memantine, 10 µM during 24 hours, restored the activities of PP-2A, CaMKII, and tau phosphorylation at Ser262 to normal levels. Memantine had no effect on the activities of either PP-2A or CaMKII in normal slice cultures. Immunohistochemical staining showed dystrophic neurites with characteristic beaded uneven contour. Memantine-treated slices showed inhibition of this degeneration.
Conclusion: These findings suggest that memantine reverses PP-2A inhibition-induced phosphorylation/dephosphorylation imbalance, tau hyperphosphorylation and associated neurodegeneration by restoring tau phosphatase and kinase activities to normal levels.
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