Increasing Cu bioavailability inhibits Aβ oligomers and tau phosphorylation

被引：235

作者：

Crouch, Peter J. ^{[1
,2
,3
]}

Hung, Lin Wai ^{[1
,3
,4
]}

Adlard, Paul A. ^{[3
]}

Cortes, Mikhalina ^{[3
]}

Lal, Varsha ^{[3
]}

Filiz, Gulay ^{[1
,2
,3
]}

Perez, Keyla A. ^{[1
,3
,4
]}

Nurjono, Milawaty ^{[3
]}

Caragounis, Aphrodite ^{[1
,2
,3
]}

Du, Tai ^{[1
,2
,3
]}

Laughton, Katrina ^{[1
,3
]}

Volitakis, Irene ^{[1
,3
]}

Bush, Ashley I. ^{[3
]}

Li, Qiao-Xin ^{[1
,2
,3
]}

Masters, Colin L. ^{[3
]}

Cappai, Roberto ^{[1
,3
,4
]}

Cherny, Robert A. ^{[3
]}

Donnelly, Paul S. ^{[4
,5
]}

White, Anthony R. ^{[1
,2
,3
]}

Barnham, Kevin J. ^{[1
,3
,4
]}

机构：

[1] Univ Melbourne, Dept Pathol, Melbourne, Vic 3010, Australia

[2] Univ Melbourne, Ctr Neurosci, Melbourne, Vic 3010, Australia

[3] Univ Melbourne, Sch Chem, Melbourne, Vic 3010, Australia

[4] Univ Melbourne, Bio Mol Sci & Biotechnol Inst 21, Melbourne, Vic 3010, Australia

[5] Mental Hlth Res Inst Victoria, Parkville, Vic 3052, Australia

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 02期

基金：

澳大利亚研究理事会; 澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

Alzheimer's disease; bioinorganic chemistry; glycogen synthase kinase; therapeutic; animal model; GLYCOGEN-SYNTHASE KINASE-3; IMPAIR SYNAPTIC PLASTICITY; AMYLOID PRECURSOR PROTEIN; LONG-TERM POTENTIATION; ALZHEIMERS-DISEASE; TRANSGENIC MICE; MEDIATED NEURODEGENERATION; SOLUBLE OLIGOMERS; UP-REGULATION; COPPER;

D O I：

10.1073/pnas.0809057106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Cognitive decline in Alzheimer's disease (AD) involves pathological accumulation of synaptotoxic amyloid-beta (A beta) oligomers and hyperphosphorylated tau. Because recent evidence indicates that glycogen synthase kinase 3 beta (GSK3 beta) activity regulates these neurotoxic pathways, we developed an AD therapeutic strategy to target GSK3 beta. The strategy involves the use of copper-bis(thiosemicarbazonoto) complexes to increase intracellular copper bioavailability and inhibit GSK3 beta through activation of an Akt signaling pathway. Our lead compound Cu-II(gtsm) significantly inhibited GSK3 beta in the brains of APP/PS1 transgenic AD model mice. Cu-II(gtsm) also decreased the abundance of A beta 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 A beta trimer levels. This study demonstrates that increasing intracellular copper bioavailability can restore cognitive function by inhibiting the accumulation of neurotoxic A beta trimers and phosphorylated tau.

引用

页码：381 / 386

页数：6

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