Temporal correlation of the memory deficit with Alzheimer-like lesions induced by activation of glycogen synthase kinase-3.
We have reported that activation of glycogen synthase kinase-3 (GSK-3) by ventricle injection of wortmannin (WT) and GF-109203X (GFX) induces Alzheimer-like memory deficit in rats [Liu et al., J. Neurochem. 87 (2003), 1333]. To further explore the factors responsible for the memory loss, we studied here the temporal alterations of GSK-3, tau phosphorylation, beta-amyloid (Abeta), and acetylcholine (ACh) after injection of WT/GFX, and analyzed their correlation with the memory loss. We observed that the severe memory deficit occurred at 24 and 48 h, and simultaneously, GSK-3 activation, tau hyperphosphorylation at Thr231, Ser396, and Ser404 and decline of ACh in hippocampus were detected, and these changes were mostly recovered at 72 and 96 h after the injection of WT/GFX. Remarkable increase of Abeta and intracellular accumulation of argentophilic substances were detected at 72 h. Pearson analysis showed that the memory deficit was correlated with GSK-3 activation, tau hyperphosphorylation, and decline of ACh but not with Abeta overproduction. Our data provide direct evidence demonstrating that activation of GSK-3 by WT/GFX may cause memory deficit through tau hyperphosphorylation and suppression of ACh in hippocampus.
Wang
Yue
Y
Department of Pathophysiology, Key Laboratory of Neurological Disease of National Education Committee, Tongji Medical College, Huazhong University of Science and Technical, Wuhan, China.
Zhang
Jun-Xia
JX
Du
Xiao-Xia
XX
Zhao
Li
L
Tian
Qing
Q
Zhu
Ling-Qiang
LQ
Wang
Shao-Hui
SH
Wang
Jian-Zhi
JZ
D000109:Acetylcholine / Q000378:metabolism; D000544:Alzheimer Disease / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D000595:Amino Acid Sequence / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000378:metabolism*; D006624:Hippocampus / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008569:Memory Disorders / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D058225:Plaque, Amyloid / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D000077191:Wortmannin; D016875:tau Proteins / Q000187:drug effects / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000730:Androstadienes; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D016875:tau Proteins; D038362:Glycogen Synthase Kinase 3; C070515:bisindolylmaleimide I; D000109:Acetylcholine; D000077191:Wortmannin