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 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.



Alzheimer Disease, CDK(Cyclin-dependent kinase), Glycogen Synthase Kinase 3, Neurodegenerative diseases, Protein Phosphorylation, Kinase Inhibitor, Tauopathy


Copyright 2013 Journal of Biological Chemistry. Recommended citation: Zhang, Xuemei, Israel Hernandez, Damien Rei, Waltraud Mair, Joydev K. Laha, Madison E. Cornwell, Gregory D. Cuny, Li-Huei Tsai, Judith AJ Steen, and Kenneth S. Kosik. "Diaminothiazoles modify Tau phosphorylation and improve the tauopathy in mouse models." Journal of Biological Chemistry 288, no. 30 (2013): 22042-22056.doi: 10.1074/jbc.M112.436402. URL: http://www.jbc.org/content/288/30/22042. Reproduced in accordance with the original publisher's licensing terms and with permission from the authors.