Inhibition of glycogen synthase kinase-3β downregulates total tau proteins in cultured neurons and its reversal by the blockade of protein phosphatase-2A

• Published in: Brain research 2009-02, Vol.1252, p.66-75
• Main Authors: Martin, Ludovic, Magnaudeix, Amandine, Esclaire, Françoise, Yardin, Catherine, Terro, Faraj
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Glycogen synthase kinase-3β; Lithium; Neurology; Protein phosphatase-2A; Protein phosphatase-2B; Tau
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2008.11.057

Abstract In tauopathies such as Alzheimer's disease (AD), the molecular mechanisms of tau protein aggregation into neurofibrillary tangles (NFTs) and their contribution to neurodegeneration remain not understood. It was recently demonstrated that tau, regardless of its aggregation, might represent a key mediator of neurodegeneration. Therefore, reduction of tau levels might represent a mechanism of neuroprotection. Glycogen synthase kinase-3β (GSK3β) and protein phosphatase-2A (PP2A) are key enzymes involved in the regulation of tau phosphorylation, and have been suggested to be involved in the abnormal tau phosphorylation and aggregation in AD. Connections between PP2A and GSK3β signaling have been reported. We have previously demonstrated that exposure of cultured cortical neurons to lithium decreased tau protein expression and provided neuroprotection against Aβ. Since lithium is not a specific inhibitor of GSK3β (ID50 = 2.0 mM), whether or not the lithium-induced tau decrease involves GSK3β remained to be determined. For that purpose, cultured cortical neurons were exposed to 6-bromo-indirubin-3′-oxime (6-BIO), a more selective and potent GSK3β inhibitor (ID50 = 1.5 µM) or to lithium. Analysis of tau levels and phosphorylation by western-blot assays showed that lithium and 6-BIO dose-dependently decreased both tau protein levels and tau phosphorylation. Conversely, inhibition of cyclin-dependent kinase-5 (CDK5) by roscovitine decreased phosphorylated tau but failed to alter tau protein levels. These data indicate that GSK3β might be selectively involved in the regulation of tau protein levels. Moreover, inhibition of PP2A by okadaic acid, but not that of PP2B (protein phosphatase-2B)/calcineurin by FK506, dose-dependently reversed lithium-induced tau decrease. These data indicate that GSK3β regulates both tau phosphorylation and total tau levels through PP2A.