| Autor: |
Zhang X; Neuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California at Santa Barbara, Santa Barbara, California 93106, USA., Hernandez I, Rei D, Mair W, Laha JK, Cornwell ME, Cuny GD, Tsai LH, Steen JA, Kosik KS |
| Jazyk: |
angličtina |
| Zdroj: |
The Journal of biological chemistry [J Biol Chem] 2013 Jul 26; Vol. 288 (30), pp. 22042-56. Date of Electronic Publication: 2013 Jun 04. |
| DOI: |
10.1074/jbc.M112.436402 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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