Unknown

Dataset Information

0

Increasing Cu bioavailability inhibits Abeta oligomers and tau phosphorylation.


ABSTRACT: 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 Abeta 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 Abeta trimer levels. This study demonstrates that increasing intracellular copper bioavailability can restore cognitive function by inhibiting the accumulation of neurotoxic Abeta trimers and phosphorylated tau.

SUBMITTER: Crouch PJ 

PROVIDER: S-EPMC2626711 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

altmetric image

Publications


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 act  ...[more]

Similar Datasets

| S-EPMC6633549 | biostudies-literature
| S-EPMC9337746 | biostudies-literature
| S-EPMC7824853 | biostudies-literature
| S-EPMC137848 | biostudies-literature
| S-EPMC4049638 | biostudies-literature
| S-EPMC3784324 | biostudies-literature
| S-EPMC2680286 | biostudies-literature
| S-EPMC3024010 | biostudies-literature
| S-EPMC2896418 | biostudies-other
| S-EPMC8199196 | biostudies-literature