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首页> 外文期刊>Archives of Toxicology >Cadmium-induced cell death of basal forebrain cholinergic neurons mediated by muscarinic M1 receptor blockade, increase in GSK-3 beta enzyme, beta-amyloid and tau protein levels
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Cadmium-induced cell death of basal forebrain cholinergic neurons mediated by muscarinic M1 receptor blockade, increase in GSK-3 beta enzyme, beta-amyloid and tau protein levels

机译：毒蕈碱M1受体阻滞介导的镉诱导的基础前脑胆碱能神经元细胞死亡，GSK-3β酶，β-淀粉样蛋白和tau蛋白水平的升高

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Cadmium is a neurotoxic compound which induces cognitive alterations similar to those produced by Alzheimer's disease (AD). However, the mechanism through which cadmium induces this effect remains unknown. In this regard, we described in a previous work that cadmium blocks cholinergic transmission and induces a more pronounced cell death on cholinergic neurons from basal forebrain which is partially mediated by AChE overexpression. Degeneration of basal forebrain cholinergic neurons, as happens in AD, results in memory deficits attributable to the loss of cholinergic modulation of hippocampal synaptic circuits. Moreover, cadmium has been described to activate GSK-3 beta, induce A beta protein production and tau filament formation, which have been related to a selective loss of basal forebrain cholinergic neurons and development of AD. The present study is aimed at researching the mechanisms of cell death induced by cadmium on basal forebrain cholinergic neurons. For this purpose, we evaluated, in SN56 cholinergic mourine septal cell line from basal forebrain region, the cadmium toxic effects on neuronal viability through muscarinic M1 receptor, AChE splice variants, GSK-3 beta enzyme, A beta and tau proteins. This study proves that cadmium induces cell death on cholinergic neurons through blockade of M1 receptor, overexpression of AChE-S and GSK-3 beta, down-regulation of AChE-R and increase in A beta and total and phosphorylated tau protein levels. Our present results provide new understanding of the mechanisms contributing to the harmful effects of cadmium on cholinergic neurons and suggest that cadmium could mediate these mechanisms by M1R blockade through AChE splices altered expression.
机译：镉是一种神经毒性化合物，可诱发类似于阿尔茨海默氏病（AD）产生的认知改变。但是，镉诱导这种作用的机理尚不清楚。在这方面，我们在先前的工作中描述了镉阻断胆碱能的传递并在基底前脑的胆碱能神经元上诱导更明显的细胞死亡，这部分是由AChE过表达介导的。基底前脑胆碱能神经元的变性，如发生在AD中，会导致记忆缺陷，这归因于海马突触回路胆碱能调节的丧失。而且，已经描述了镉激活GSK-3β，诱导Aβ蛋白产生和tau细丝形成，这与基底前脑胆碱能神经元的选择性丧失和AD的发展有关。本研究旨在研究镉诱导的基底前脑胆碱能神经元细胞死亡的机制。为此，我们评估了来自前脑基底区的SN56胆碱能鼠间隔细胞系中镉对毒蕈碱M1受体，AChE剪接变体，GSK-3β酶，Aβ和tau蛋白对神经元活力的毒性作用。这项研究证明，镉可通过阻断M1受体，AChE-S和GSK-3 beta的过度表达，AChE-R的下调以及A beta以及总tau蛋白和磷酸化tau蛋白水平的升高来诱导胆碱能神经元细胞死亡。我们目前的结果提供了新的认识，对造成镉对胆碱能神经元的有害作用的机制，并建议镉可以通过AChE剪接改变表达的M1R阻断介导这些机制。

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