Effect of melatonin on calyculin A-induced tau hyperphosphorylation.
We have found in the present study that incubation of neuroblastma N2a with calyculin A, an inhibitor of protein phosphatase-2A (PP-2A) and protein phosphatase-1 (PP-1), reduces cell viability in a dose-dependent manner, and leads to tau hyperphosphorylation at tau-1 (Ser198/199/202) and PHF-1 (Ser396/404) epitopes. In addition to inhibit PP-2A, calyculin A treatment also results in significant activation of glycogen synthase kinase-3 (GSK-3). Calyculin A induces oxidative stress manifested by elevated level of malondialdehyde and decreased activity of superoxide dismutase. When the cells were incubated simultaneously with calyculin A and melatonin (25 microM or 50 microM), the calyculin A-induced decrease in cell viability, tau hyperphosphorylation, PP-2A/GSK-3 imbalance and oxidative stress were attenuated accordingly. These results suggest (i) that calyculin A induces tau hyperphosphorylation not only by inhibition of PP-2A, but also by activation of GSK-3 in N2a cells; (ii) that melatonin efficiently attenuates the calyculin A-induced damages through not only its antioxidant effect but also its modulation to the phosphorylation system.
Li
Xia-Chun
XC
Department of Pathophysiology, Institute of Neuroscience, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
Wang
Ze-Fen
ZF
Zhang
Jun-Xia
JX
Wang
Qun
Q
Wang
Jian-Zhi
JZ
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D008387:Marine Toxins; D008550:Melatonin / Q000494:pharmacology*; D010080:Oxazoles / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D016875:tau Proteins / Q000378:metabolism*
D008387:Marine Toxins; D010080:Oxazoles; D016875:tau Proteins; D008315:Malondialdehyde; C059041:calyculin A; D038362:Glycogen Synthase Kinase 3; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D008550:Melatonin