Overactivation of glycogen synthase kinase-3 by inhibition of phosphoinositol-3 kinase and protein kinase C leads to hyperphosphorylation of tau and impairment of spatial memory.
Neurofibrillary tangles (NFTs) consisting of the hyperphosphorylated microtubule-associated protein tau are a defining pathological characteristic of Alzheimer's disease (AD). Hyperphosphorylation of tau is hypothesized to impair the microtubule stabilizing function of tau, leading to the formation of paired helical filaments and neuronal death. Glycogen synthase kinase-3 (GSK-3) has been shown to be one of several kinases that mediate tau hyperphosphorylation in vitro. However, molecular mechanisms underlying overactivation of GSK-3 and its potential linkage to AD-like pathologies in vivo remain unclear. Here, we demonstrate that injection of wortmannin (a specific inhibitor of phosphoinositol-3 kinase) or GF-109203X (a specific inhibitor of protein kinase C) into the left ventricle of rat brains leads to overactivation of GSK-3, hyperphosphorylation of tau at Ser 396/404/199/202 and, most significantly, impaired spatial memory. The effects of wortmannin and GF-109203X are additive. Significantly, specific inhibition of GSK-3 activity by LiCl prevents hyperphosphorylation of tau, and spatial memory impairment resulting from PI3K and PKC inhibition. These results indicate that in vivo inhibition of phosphoinositol-3 kinase and protein kinase C results in overactivation of GSK-3 and tau hyperphosphorylation and support a direct role of GSK-3 in the formation of AD-like cognitive deficits.
Liu
Shi Jie
SJ
Pathophysiology Department, Neuroscience Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Zhang
Ai Hong
AH
Li
Hong Lian
HL
Wang
Qun
Q
Deng
Heng Mei
HM
Netzer
William J
WJ
Xu
Huaxi
H
Wang
Jian Zhi
JZ
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004924:Escape Reaction / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000201:enzymology* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D012694:Serine / Q000378:metabolism; D000077191:Wortmannin; D016875:tau Proteins / Q000378:metabolism*
D000730:Androstadienes; D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; C085349:PHF-1 monoclonal antibody; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016875:tau Proteins; D012694:Serine; D011493:Protein Kinase C; D038362:Glycogen Synthase Kinase 3; C070515:bisindolylmaleimide I; D000077191:Wortmannin