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.
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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)
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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
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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)
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