title: Tau phosphorylation and neuronal apoptosis induced by the blockade of PP2A preferentially involve GSK3β.
abstract: Overactivation of GSK3β (glycogen synthase kinase-3β) and downregulation of PP2A (protein phosphatase-2A) have been proposed to be involved in the abnormal tau phosphorylation and aggregation in Alzheimer's disease (AD). GSK3β and PP2A signaling pathways were reported to be interconnected. Targeting tau kinases was suggested to represent a therapeutic strategy for AD. Here, tau phosphorylation and neuronal apoptosis were induced in cortical cultured neurons by the inhibition of PP2A by okadaic acid (OKA). In this in vitro model of 'tau pathology' and neurodegeneration, we tested whether GSK3β and other tau kinases including DYRK1A and CDK5 were implicated. Our results show that the inhibitors of GSK3β, lithium and 6-BIO (6-bromoindirubin-3'-oxime), prevented OKA-induced tau phosphorylation and neuronal apoptosis. The implication of GSK3β in these OKA-induced effects was confirmed by its silencing by hairpin siRNA. By contrast, inhibition of DYRK1A (dual-specificity tyrosine-phosphorylation regulated kinase-1A) and CDK5 (cyclin-dependent kinase-5) reversed OKA-induced tau phosphorylation at certain sites but failed to prevent neuronal apoptosis. These results indicate that OKA-induced effects, especially neuronal apoptosis, are preferentially mediated by GSK3β. Furthermore, since chronic exposure to lithium and 6-BIO might be deleterious for neurons, we tested the effect of a new 6-BIO derivative, 6-BIBEO (6-bromoindirubin-3'-(2-bromoethyl)-oxime), which is much less cytotoxic and more selectively inhibits GSK3β compared to lithium and 6-BIO. We show that 6-BIBEO efficiently reversed OKA-induced tau phosphorylation and neuronal apoptosis. It will be interesting to test neuroprotection by 6-BIBEO in an in vivo model of tau pathology and neurodegeneration.
authors.affiliation: Groupe de Neurobiologie Cellulaire-EA3842, Homéostasie cellulaire et pathologies, Faculté de Médecine, 2 rue du Dr Raymond Marcland, 87025 Limoges Cedex, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Martin
authors.forename: Guylene
authors.initials: G
authors.lastname: Page
authors.forename: Faraj
authors.initials: F
authors.lastname: Terro
mesh_terms: D000818:Animals; D017209:Apoptosis; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D009474:Neurons / Q000473:pathology*; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2