Browsing by Author "Steen, Judith A. J."
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Item Diaminothiazoles Modify Tau Phosphorylation and Improve the Tauopathy in Mouse Models(Journal of BIological Chemistry, 2013-07) Zhang, Xuemei; Hernandez, Israel; Rei, Damien; Mair, Waltraud; Laha, Joydev K.; Cornwell, Madison E.; Cuny, Gregory D.; Tsai, Li-Huei; Steen, Judith A. J.; Kosik, Kenneth S.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 GSK3?. Lead compounds from the series have IC50 values toward CDK5/p25 and GSK3? 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 GSK3? to Tau phosphorylation, effective treatment of tauopathies may require dual kinase targeting.