tau kinases in the rat heat shock model: possible implications for Alzheimer disease.
We have previously shown, by using the phosphate-dependent anti-tau antibodies Tau-1 and PHF-1, that heat shock induces rapid dephosphorylation of tau followed by hyperphosphorylation in female rats. In this study, we analyzed in forebrain homogenates from female Sprague-Dawley rats the activities of extracellular signal regulated kinase 1/2 (ERK1/2), c-Jun NH(2)-terminal kinase (JNK), glycogen synthase kinase-3beta (GSK-3beta), cyclin-dependent kinase 5 (Cdk5), cAMP-dependent protein kinase A (PKA), and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) at 0 (n = 5), 3 (n = 4), 6 (n = 5), and 12 (n = 5) h after heat shock and in non-heat-shocked controls (n = 5). Immunoprecipitation kinase assays at 0 h showed suppression of the activities of all kinases except of GSK-3beta, which showed increased activity. At 3-6 h, the activities of ERK1/2, JNK, Cdk5, and GSK-3beta toward selective substrates were increased; however, only JNK, Cdk5, and GSK-3beta but not ERK1/2 were overactivated toward purified bovine tau. At 3-6 h, kinase assays specific for PKA and CaMKII showed no increased activity toward either tau or selective substrates. All of eight anti-tau antibodies tested showed dephosphorylation at 0 h and hyperphosphorylation at 3-6 h, except for 12E8, which showed hyperphosphorylation also at 0 h. Immunoblot analysis using activity-dependent antibodies against ERK1/2, JNK, and GSK-3beta confirmed the above data. Increased activation and inhibition of kinases after heat shock were statistically significant in comparison with controls. Because tau is hyperphosphorylated in Alzheimer disease these findings suggest that JNK, GSK-3beta, and Cdk5 may play a role in its pathogenesis.
Shanavas
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Department of Pathology and Laboratory Medicine, University of Texas-Houston Medical School, Houston, TX 77030, USA.
Papasozomenos
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D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002417:Cattle; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D005260:Female; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response; D015151:Immunoblotting / Q000379:methods; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D016875:tau Proteins / Q000302:isolation & purification / Q000378:metabolism*
D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D016875:tau Proteins; D038341:Glycogen Synthase Kinases; D051360:Cyclin-Dependent Kinase 5; D017868:Cyclic AMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C495907:Cdk5 protein, rat; D018844:Cyclin-Dependent Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3