| Autor: |
Crouch, Peter J., Lin Wai Hung, Adlard, Paul A., Cortes, Mikhalina, LaI, Varsha, FiIiz, Gulay, Perez, Keyla A., Nurjono, Milawaty, Caragounis, Aphrodite, Tai Du, Laughton, Katrina, Volitakis, Irene, Bush, Ashley I., Qiao-Xin Li, Masters, Cohn L., Cappai, Roberto, Cherny, Robert A., DonneIly, Paul S., White, Anthony R., Barnham, Kevin J. |
| Předmět: |
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| Zdroj: |
Proceedings of the National Academy of Sciences of the United States of America; 1/13/2009, Vol. 106 Issue 2, p381-386, 6p, 1 Color Photograph, 2 Diagrams, 7 Graphs |
| Abstrakt: |
Cognitive decline in Alzheimer's disease (AD) involves pathological accumulation of synaptotoxic amyloid-β (Aβ) oligomers and hyperphosphorylated tau. Because recent evidence indicates that glycogen synthase kinase 3β (GSK3β) activity regulates these neurotoxic pathways, we developed an AD therapeutic strategy to target GSK3β. The strategy involves the use of copper-bis(thiosemicarbazonoto) complexes to increase intracellular copper bioavailability and inhibit GSK3β through activation of an Akt signaling pathway. Our lead compound Cu[supII](gtsm) significantly inhibited GSK3β in the brains of APP/PSi transgenic AD model mice. Cu[supII](gtsm) also decreased the abundance of Aβ trimers and phosphorylated tau, and restored performance of AD mice in the Y-maze test to levels expected for cognitively normal animals. Improvement in the Y-maze correlated directly with decreased Aβ trimer levels. This study demonstrates that increasing intracellular copper bioavailability can restore cognitive function by inhibiting the accumulation of neurotoxic Aβ trimers and phosphorylated tau. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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