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.

砷是一种准金属，被认为是阿尔茨海默氏病（AD）的环境危险因素，该疾病具有高磷酸化tau聚集体作为标志物。本研究表明，在低微摩尔范围（1-10μM）下长时间暴露于亚砷酸钠会降低分化的人成神经细胞瘤SH-SY5Y细胞中的Tau 1（可识别残基189-207处的去磷酸化tau）和pS202 tau升高，表明砷会增加tau神经元中的磷酸化。亚砷酸钠提高了GSK3β激酶的活性，而GSK3抑制剂BIO，SB216763和锂则逆转了亚砷酸钠对Tau 1的还原作用。此外，亚砷酸钠提高了ERK1 / 2的活性磷酸化水平，而U0126抑制ERK1 / 2则部分改善了Tau1的降低。这些结果表明，砷可能通过激活GSK3和ERK1 / 2引起神经元中tau蛋白的过度磷酸化。此外，亚砷酸钠增强了膜和胞质组分中的tau磷酸化。在膜级分中观察到了亚砷酸钠处理诱导的GSK3活性的诱导，这是由β-catenin的减少所证明的，β-catenin是一种信号蛋白，被GSK3磷酸化后降解。在细胞质中也观察到亚砷酸钠增强了ERK1 / 2磷酸化。另外，亚砷酸钠增加不溶性tau聚集。这些结果表明，砷在膜级分中诱导tau过度磷酸化，这可能导致砷从膜级分重新分布到细胞质中，从而促进神经原纤维形成。总的来说，