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Chronic Arsenic Exposure Increases Aβ(1–42) Production and Receptor for Advanced Glycation End Products Expression in Rat Brain
Chemical Research in Toxicology ( IF 4.1 ) Pub Date : 2017-12-04 00:00:00 , DOI: 10.1021/acs.chemrestox.7b00215
Sandra Aurora Niño , Guadalupe Martel-Gallegos , Adriana Castro-Zavala , Benita Ortega-Berlanga , Juan Manuel Delgado , Héctor Hernández-Mendoza 1, 2 , Elizabeth Romero-Guzmán 1 , Judith Ríos-Lugo , Sergio Rosales-Mendoza , María E. Jiménez-Capdeville , Sergio Zarazúa
Affiliation  

Chronic arsenic exposure during development is associated with alterations of chemical transmission and demyelination, which result in cognitive deficits and peripheral neuropathies. At the cellular level, arsenic toxicity involves increased generation of reactive species that induce severe cellular alterations such as DNA fragmentation, apoptosis, and lipid peroxidation. It has been proposed that arsenic-associated neurodegeneration could evolve to Alzheimer disease in later life.1,2 In this study, the effects of chronic exposure to inorganic arsenic (3 ppm by drinking water) in Wistar rats on the production and elimination of Amyloid-β (Aβ) were evaluated. Male Wistar rats were exposed to 3 ppm of arsenic in drinking water from fetal development until 4 months of age. After behavioral deficits induced by arsenic exposure through contextual fear conditioning were verified, the brains were collected for the determination of total arsenic by inductively coupled plasma-mass spectrometry, the levels of amyloid precursor protein and receptor for advanced glycation end products (RAGE) by Western blot analysis as well as their transcript levels by RT-qPCR, Aβ(1–42) estimation by ELISA assay and the enzymatic activity of β-secretase (BACE1). Our results demonstrate that chronic arsenic exposure induces behavioral deficits accompanied of higher levels of soluble and membranal RAGE and the increase of Aβ(1–42) cleaved. In addition, BACE1 enzymatic activity was increased, while immunoblot assays showed no differences in the low-density lipoprotein receptor-related protein 1 (LRP1) receptor among groups. These results provide evidence of the effects of arsenic exposure on the production of Aβ(1–42) and cerebral amyloid clearance through RAGE in an in vivo model that displays behavioral alterations. This work supports the hypothesis that early exposure to metals may contribute to neurodegeneration associated with amyloid accumulation.

中文翻译:

慢性砷暴露增加大鼠脑中高级糖基化终产物表达的Aβ (1-42)产生和受体

发育过程中的慢性砷暴露与化学传递和脱髓鞘改变有关,这导致认知缺陷和周围神经病。在细胞水平上,砷毒性涉及增加反应性物质的产生,这些反应性物质会引起严重的细胞变化,例如DNA片段化,细胞凋亡和脂质过氧化。有人提出砷相关的神经退行性变可能在以后的生活中演变成阿尔茨海默病。1,2在这项研究中,Wistar大鼠长期暴露于无机砷(饮用水中3 ppm)对淀粉样蛋白产生和消除的影响评估-β(Aβ)。从胎儿发育到4个月大,雄性Wistar大鼠在饮用水中接触3 ppm的砷。(1-42)通过ELISA测定和β-分泌酶(BACE1)的酶活性进行估算。我们的结果表明,慢性砷暴露会导致行为缺陷,伴随着较高水平的可溶性和膜RAGE以及裂解的Aβ (1-42)增加。此外,BACE1的酶活性增加,而免疫印迹试验显示低密度脂蛋白受体相关蛋白1(LRP1)受体之间没有差异。这些结果提供的砷暴露于Aβ产生的影响的证据(1-42)在一个和脑淀粉样蛋白通过间隙RAGE体内显示行为改变的模型。这项工作支持这样的假设,即金属的早期暴露可能会导致与淀粉样蛋白积累有关的神经退行性变。
更新日期:2017-12-04
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