Chronic oxidative stress causes increased tau phosphorylation in M17 neuroblastoma cells.
Tau hyperphosphorylation appears to be a critical event leading to abnormal aggregation and disrupted function of tau in affected neurons in Alzheimer's disease (AD). As a prominent early event during AD pathogenesis, oxidative stress is believed to contribute to tau phosphorylation and the formation of neurofibrillary lesions. However, acute oxidative stress has disparate effects on tau phosphorylation. Given the chronic nature of AD, in this study, we aimed to determine the long-term effect of oxidative stress on tau phosphorylation. In this regard, we established a novel in vitro model of chronic oxidative stress through inhibition of glutathione (GSH) synthesis with BSO. We confirmed that these cells were under a chronic mild oxidative stress by looking at oxidative response, the induction of heme oxygenase 1 (HO-1) without neuronal death. Chronic oxidative stress increased levels of tau phosphorylated at PHF-1 epitope (serine 399/404) in a time-dependent manner. Our data further suggest that increased activity of JNK and p38 and decreased activity of PP2A are likely involved in chronic oxidative stress-induced tau phosphorylation. In conclusion we suggest that chronic oxidative stress contributes to increased tau phosphorylation in vitro and could play a critical role in neurofibrillary pathology in vivo.
Su
Bo
B
Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH 44106, USA.
Wang
Xinglong
X
Lee
Hyoung-Gon
HG
Tabaton
Massimo
M
Perry
George
G
Smith
Mark A
MA
Zhu
Xiongwei
X
D019328:Buthionine Sulfoximine / Q000494:pharmacology; D045744:Cell Line, Tumor; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009447:Neuroblastoma; D018384:Oxidative Stress; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D016875:tau Proteins; D019328:Buthionine Sulfoximine; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054648:Protein Phosphatase 2; D005978:Glutathione