Increasing Cu bioavailability inhibits A beta oligomers and tau phosphorylation
Peter J Crouch, Lin Wai Hung, Paul A Adlard, Mikhalina Cortes, Varsha Lal, Gulay Filiz, Keyla A Perez, Milawaty Nurjono, Aphrodite Caragounis, Tai Du, Katrina Laughton, Irene Volitakis, Ashley I Bush, Qiao-Xin Li, Colin L Masters, Roberto Cappai, Robert A Cherny, Paul S Donnelly, Anthony R White, Kevin J Barnham
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | NATL ACAD SCIENCES | Published : 2009
Cognitive decline in Alzheimer's disease (AD) involves pathological accumulation of synaptotoxic amyloid-beta (Abeta) oligomers and hyperphosphorylated tau. Because recent evidence indicates that glycogen synthase kinase 3beta (GSK3beta) activity regulates these neurotoxic pathways, we developed an AD therapeutic strategy to target GSK3beta. The strategy involves the use of copper-bis(thiosemicarbazonoto) complexes to increase intracellular copper bioavailability and inhibit GSK3beta through activation of an Akt signaling pathway. Our lead compound Cu(II)(gtsm) significantly inhibited GSK3beta in the brains of APP/PS1 transgenic AD model mice. Cu(II)(gtsm) also decreased the abundance of Abe..View full abstract
This work was supported by the National Health and Medical Research Council (NHMRC Program Grant), the Australian Research Council, the ANZ Charitable Trusts (Wicking Trust), and the University of Melbourne (Early Career Researcher Grant Scheme). K. J. B., A. R. W., R. C., and P. A. are NHMRC Fellows. A. I. B. is a current Australian Research Council Fellow. Dr. Giuseppe Ciccotosto kindly provided text for the LTP materials and methods.