Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo
| Autor: | Yi Wen, John LaFrancois, Mark P. Burns, Boris Feinstein, Wendy Noble, Karen Duff, Vicki Olm, Lili Wang, Kate Gaynor, Pavan Krishnamurthy, Ratan Bhat, Jada Lewis, Dennis W. Dickson, Farhana Suleman, Cindy Zehr, Jordana L Meyerson, Emmanuel Planel |
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| Rok vydání: | 2005 |
| Předmět: |
Genetically modified mouse
Lithium (medication) Tau protein Immunoblotting Mice Transgenic tau Proteins Lithium Epitopes Glycogen Synthase Kinase 3 Mice GSK-3 medicine Image Processing Computer-Assisted Animals Humans Immunoprecipitation Enzyme Inhibitors Phosphorylation Glycogen synthase Neurons Multidisciplinary biology Kinase Chemistry Neurodegenerative Diseases Biological Sciences medicine.disease Immunohistochemistry Cell biology Biochemistry Tauopathies biology.protein Disease Progression Tauopathy Lithium Chloride medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 102(19) |
| ISSN: | 0027-8424 |
| Popis: | Neurofibrillary tangles composed of hyperphosphorylated, aggregated tau are a common pathological feature of tauopathies, including Alzheimer's disease. Abnormal phosphorylation of tau by kinases or phosphatases has been proposed as a pathogenic mechanism in tangle formation. To investigate whether kinase inhibition can reduce tauopathy and the degeneration associated with it in vivo , transgenic mice overexpressing mutant human tau were treated with the glycogen synthase kinase-3 (GSK-3) inhibitor lithium chloride. Treatment resulted in significant inhibition of GSK-3 activity. Lithium administration also resulted in significantly lower levels of phosphorylation at several epitopes of tau known to be hyperphosphorylated in Alzheimer's disease and significantly reduced levels of aggregated, insoluble tau. Administration of a second GSK-3 inhibitor also correlated with reduced insoluble tau levels, supporting the idea that lithium exerts its effect through GSK-3 inhibition. Levels of aggregated tau correlated strongly with degree of axonal degeneration, and lithium-chloride-treated mice showed less degeneration if administration was started during early stages of tangle development. These results support the idea that kinases are involved in tauopathy progression and that kinase inhibitors may be effective therapeutically. |
| Databáze: | OpenAIRE |
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