Diaminothiazoles modify Tau phosphorylation and improve the tauopathy in mouse models

  • J Biol Chem. 2013 Jul 26;288(30):22042-56. doi: 10.1074/jbc.M112.436402.
Xuemei Zhang  1 ,  Israel Hernandez ,  Damien Rei ,  Waltraud Mair ,  Joydev K Laha ,  Madison E Cornwell ,  Gregory D Cuny ,  Li-Huei Tsai ,  Judith A J Steen ,  Kenneth S Kosik
Affiliations
  • 1. Neuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California at Santa Barbara, Santa Barbara, California 93106, USA.
PMID: 23737518 DOI: 10.1074/jbc.M112.436402
Abstract

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.

Keywords
Alzheimer Disease; CDK (Cyclin-dependent Kinase); Glycogen Synthase Kinase 3; Kinase Inhibitor; Neurodegenerative Diseases; Protein Phosphorylation; Tauopathy.
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