Diaminothiazoles Modify Tau Phosphorylation and Improve the Tauopathy in Mouse Models*

Although Tau accumulation is a feature of several neurodegenerative conditions, treatment options for these conditions are nonexistent. Targeting Tau kinases represents a potential therapeutic approach. Small molecules in the diaminothiazole class are potent Tau kinase inhibitors that target CDK5 and GSK3β. Lead compounds from the series have IC50 values toward CDK5/p25 and GSK3β in the low nanomolar range and no observed toxicity in the therapeutic dose range. Neuronal protective effects and decreased PHF-1 immunoreactivity were observed in two animal models, 3×Tg-AD and CK-p25. Treatment nearly eliminated Sarkosyl-insoluble Tau with the most prominent effect on the phosphorylation at Ser-404. Treatment also induced the recovery of memory in a fear conditioning assay. Given the contribution of both CDK5/p25 and GSK3β to Tau phosphorylation, effective treatment of tauopathies may require dual kinase targeting.Background: Tau is hyperphosphorylated in the tauopathies. Targeting Tau kinases CDK5 and GSK3β represents a potential therapeutic approach.Results: Inhibitors of Tau kinases are neuroprotective, decrease PHF-1 immunoreactivity, and induce recovery of memory by fear conditioning.Conclusion: Diaminothiazoles as CDK5 and GSK3β inhibitors improve the tauopathy in mouse models.Significance: Dual kinase inhibition can be critical for efficacy when treating tauopathies. Although Tau accumulation is a feature of several neurodegenerative conditions, treatment options for these conditions are nonexistent. Targeting Tau kinases represents a potential therapeutic approach. Small molecules in the diaminothiazole class are potent Tau kinase inhibitors that target CDK5 and GSK3β. Lead compounds from the series have IC50 values toward CDK5/p25 and GSK3β in the low nanomolar range and no observed toxicity in the therapeutic dose range. Neuronal protective effects and decreased PHF-1 immunoreactivity were observed in two animal models, 3×Tg-AD and CK-p25. Treatment nearly eliminated Sarkosyl-insoluble Tau with the most prominent effect on the phosphorylation at Ser-404. Treatment also induced the recovery of memory in a fear conditioning assay. Given the contribution of both CDK5/p25 and GSK3β to Tau phosphorylation, effective treatment of tauopathies may require dual kinase targeting. Background: Tau is hyperphosphorylated in the tauopathies. Targeting Tau kinases CDK5 and GSK3β represents a potential therapeutic approach. Results: Inhibitors of Tau kinases are neuroprotective, decrease PHF-1 immunoreactivity, and induce recovery of memory by fear conditioning. Conclusion: Diaminothiazoles as CDK5 and GSK3β inhibitors improve the tauopathy in mouse models. Significance: Dual kinase inhibition can be critical for efficacy when treating tauopathies. Small Molecule Kinase Inhibitors Reduce Hyperphosphorylated Tau in Alzheimer Disease Mouse Models♦: Diaminothiazoles Modify Tau Phosphorylation and Improve the Tauopathy in Mouse ModelsJournal of Biological ChemistryVol. 288Issue 30Preview♦ See referenced article, J. Biol. Chem. 2013, 288, 22042–22056 Full-Text PDF Open Access