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Arsenic is a metalloid that has been hypothesized to be an environmental risk factor for Alzheimer's disease (AD), a disease having hyperphosphorylated tau aggregate as a marker. The present study demonstrated that prolonged exposure to sodium arsenite at low micromolar range (1-10 μM) reduced Tau 1 (recognizing dephosphorylated tau at residues 189-207) and elevated pS202 tau in differentiated human neuroblastoma SH-SY5Y cells indicating that arsenic increases tau phosphorylation in neurons. Sodium arsenite elevated GSK3β kinase activity, while GSK3 inhibitors, BIO, SB216763, and lithium, reversed the Tau 1 reduction by sodium arsenite. Additionally, sodium arsenite increased levels of active phosphorylation of ERK1/2, and inhibition of ERK1/2 by U0126 partially improved the Tau1 reduction. These results suggest that arsenic may cause tau hyperphosphorylation in neurons through the activation of GSK3 and ERK1/2. Furthermore, sodium arsenite augmented tau phosphorylation in the membrane and cytosolic fractions. Inductions of GSK3 activity by sodium arsenite treatment were observed in the membrane fraction, as evidenced by a reduction of β-catenin, a protein signaled for degradation following phosphorylation by GSK3. An enhancement of ERK1/2 phosphorylation by sodium arsenite was also witnessed in the cytosol. Additionally, sodium arsenite increased insoluble tau aggregation. These results suggest that arsenic induces tau hyperphosphorylation in the membrane fraction which may lead to its redistribution from the membrane fraction to the cytosol, where it promotes neurofibrillary formation. Collectively, we demonstrate that prolonged arsenic exposure increases tau phosphorylation, partly through GSK3 and ERK1/2 activation, and insoluble tau aggregates, hence possibly contributing to the development of sporadic AD. Copyright © 2021 Elsevier B.V. All rights reserved.


Churaibhon Wisessaowapak, Daranee Visitnonthachai, Piyajit Watcharasit, Jutamaad Satayavivad. Prolonged arsenic exposure increases tau phosphorylation in differentiated SH-SY5Y cells: The contribution of GSK3 and ERK1/2. Environmental toxicology and pharmacology. 2021 May;84:103626

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PMID: 33621689

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