title: Overactivated mitogen-activated protein kinase by anisomycin induces tau hyperphosphorylation.
abstract: One of the pathological feathers of Alzheimer's disease (AD) is neurofibrillary tangles (NFTs), which consist of paired helical filaments (PHFs) formed by hyperphosphorylated microtubule-associated protein tau. To study the role of mitogen-activated protein kinase (MAPK) in tau hyperphosphorylation and the underlying mechanism, wild type mouse neuroblastoma cells (N2a) were dealt with different concentrations (0.1 microg/mL, 0.2 microg/mL and 0.4 microg/mL) of anisomycin (an activator of MAPK) for 6 h. The relationship between MAPK activity and tau phosphorylation at some Alzheimer-sites was analyzed, and the activities of protein kinase A (PKA) and glycogen synthase kinase-3 (GSK-3) were detected. The results showed that anisomycin activated MAPK in a dose-dependent manner, but tau hyperphosphorylation at Ser-198/199/202 and Ser-396/404 sites was only observed when the concentration of anisomycin was at the level of 0.4 microg/mL, and the alteration of tau phosphorylation at Ser-214 showed no significant difference in different groups. 0.2 microg/mL and 0.4 microg/mL of anisomycin led to an increase in the activity of GSK-3, respectively, but had no effect on the activity of PKA. Lithium chloride, a specific inhibitor of GSK-3, completely abolished the anisomycin-induced elevation of tau phosphorylation without any effect on the activity of MAPK. In conclusion, overactivation of MAPK up to a certain degree induces tau hyperphosphorylation at Ser-198/199/202 and Ser-396/404 sites, and this is probably related to the effect of activated GSK-3 by MAPK.
authors.affiliation: Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.forename: Jia-Yu
authors.initials: JY
authors.lastname: Zhang
authors.forename: Shi-Jie
authors.initials: SJ
authors.lastname: Liu
authors.forename: Hong-Lian
authors.initials: HL
authors.lastname: Li
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000473:pathology; D010766:Phosphorylation; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D000841:Anisomycin; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3