Laboratory of Pharmacology, Chulabhorn Research Institute, Thailand; Environmental Toxicology Program, Chulabhorn Graduate Institute, 54 Kamphaeng Phet 6 Rd, Bangkok, 10210, Thailand.
Laboratory of Pharmacology, Chulabhorn Research Institute, Thailand.
Environ Toxicol Pharmacol. 2021 May;84:103626. doi: 10.1016/j.etap.2021.103626. Epub 2021 Feb 20.
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.
砷是一种类金属，被认为是阿尔茨海默病（AD）的环境风险因素，该病的标志物是过度磷酸化的 tau 聚集体。本研究表明，长期暴露于低微摩尔浓度的亚砷酸钠（1-10 μM）会降低 Tau 1（识别残基 189-207 处去磷酸化的 tau）并升高分化的人神经母细胞瘤 SH-SY5Y 细胞中的 pS202 tau，表明砷会增加神经元中的 tau 磷酸化。亚砷酸钠会提高 GSK3β 激酶活性，而 GSK3 抑制剂 BIO、SB216763 和锂可逆转亚砷酸钠引起的 Tau 1 减少。此外，亚砷酸钠会增加 ERK1/2 的活性磷酸化水平，而 U0126 抑制 ERK1/2 可部分改善 Tau1 减少。这些结果表明，砷可能通过激活 GSK3 和 ERK1/2 导致神经元中的 tau 过度磷酸化。此外，亚砷酸钠会增加膜和细胞溶质部分的 tau 磷酸化。亚砷酸钠处理诱导 GSK3 活性增加，这可通过 β-连环蛋白（一种在 GSK3 磷酸化后被信号降解的蛋白质）减少来证明。还观察到亚砷酸钠在细胞质中增强 ERK1/2 的磷酸化。此外，亚砷酸钠增加了不溶性 tau 聚集体。这些结果表明，砷会在膜部分诱导 tau 过度磷酸化，这可能导致其从膜部分重新分布到细胞质，在细胞质中促进神经原纤维形成。总之，我们证明长期暴露于砷会增加 tau 磷酸化，部分通过 GSK3 和 ERK1/2 的激活以及不溶性 tau 聚集体，从而可能导致散发型 AD 的发生。
