Diaminothiazoles modify Tau phosphorylation and improve the tauopathy in mouse models.

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.

• Authors: Xuemei Zhang, 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
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 30 Pg. 22042-56 (Jul 26 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 23737518 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Diamines
• Neuroprotective Agents
• Presenilin-1
• Protein Kinase Inhibitors
• Thiazoles
• tau Proteins
• Cyclin-Dependent Kinase 5
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Glycogen Synthase Kinase 3

Topics

• Alzheimer Disease (genetics, metabolism, prevention & control)
• Amyloid beta-Peptides (genetics, metabolism)
• Animals
• Blotting, Western
• Cyclin-Dependent Kinase 5 (antagonists & inhibitors, genetics, metabolism)
• Diamines (chemistry)
• Disease Models, Animal
• Glycogen Synthase Kinase 3 (antagonists & inhibitors)
• Glycogen Synthase Kinase 3 beta
• Humans
• Injections, Intraperitoneal
• Injections, Intraventricular
• Injections, Subcutaneous
• Learning (drug effects)
• Male
• Memory (drug effects)
• Mice
• Mice, Transgenic
• Neuroprotective Agents (chemistry, pharmacokinetics, pharmacology)
• Phosphorylation (drug effects)
• Presenilin-1 (genetics, metabolism)
• Protein Kinase Inhibitors (administration & dosage, chemistry, pharmacology)
• Tauopathies (genetics, metabolism, prevention & control)
• Thiazoles (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• Treatment Outcome
• tau Proteins (genetics, metabolism)