Increasing Cu bioavailability inhibits Abeta oligomers and tau phosphorylation.
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.
Crouch
Peter J
PJ
Department of Pathology, Centre for Neuroscience, School of Chemistry, and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victorial, 3010, Australia.
Hung
Lin Wai
LW
Adlard
Paul A
PA
Cortes
Mikhalina
M
Lal
Varsha
V
Filiz
Gulay
G
Perez
Keyla A
KA
Nurjono
Milawaty
M
Caragounis
Aphrodite
A
Du
Tai
T
Laughton
Katrina
K
Volitakis
Irene
I
Bush
Ashley I
AI
Li
Qiao-Xin
QX
Masters
Colin L
CL
Cappai
Roberto
R
Cherny
Robert A
RA
Donnelly
Paul S
PS
White
Anthony R
AR
Barnham
Kevin J
KJ
D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D003300:Copper / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D019281:Dimerization; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D038341:Glycogen Synthase Kinases / Q000037:antagonists & inhibitors; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009942:Organometallic Compounds / Q000493:pharmacokinetics; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016875:tau Proteins / Q000187:drug effects* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D009942:Organometallic Compounds; D016875:tau Proteins; D003300:Copper; D038341:Glycogen Synthase Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3