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

• Published in: Journal of neurochemistry Vol. 87; no. 6; pp. 1333 - 1344
• Main Authors: Liu, Shi Jie, Zhang, Ai Hong, Li, Hong Lian, Wang, Qun, Deng, Heng Mei, Netzer, William J., Xu, Huaxi, Wang, Jian Zhi
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.12.2003; Blackwell
• Subjects: Alzheimer's disease; Androstadienes - pharmacology; Animals; Antibodies, Monoclonal - metabolism; Behavior, Animal - drug effects; Biological and medical sciences; Blotting, Western; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors - pharmacology; Escape Reaction - drug effects; Glycogen Synthase Kinase 3 - metabolism; glycogen synthase kinase‐3; Hippocampus - drug effects; Hippocampus - enzymology; Immunohistochemistry; Indoles - pharmacology; Injections, Intraventricular; Male; Maleimides - pharmacology; Maze Learning - drug effects; Maze Learning - physiology; Medical sciences; Memory Disorders - enzymology; Memory Disorders - metabolism; Neurology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; phosphoinositol‐3 kinase; Phosphorylation; protein kinase C; Protein Kinase C - antagonists & inhibitors; Rats; Rats, Wistar; Serine - metabolism; spatial memory; tau; tau Proteins - metabolism; Wortmannin; Protein kinase C; Rat; Alzheimer disease; Glycogen synthase kinase-3; Phosphoinositol-3 kinase; Signal transduction; Degenerative disease; Microtubule associated protein; Alzheimer's disease; Nervous system diseases; Enzyme; Transferases; Rodentia; tau; Neurofibrillary tangle; In vitro; Cerebral disorder; Vertebrata; Anatomic pathology; Mammalia; Tau protein; Animal; Central nervous system disease; Cytoskeleton; Microtubule; Spatial memory
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2003.02070.x

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.