Del Pino Javier, Zeballos Gabriela, Anadon María José, Díaz María Jesús, Moyano Paula, Díaz Gloria Gómez, García Jimena, Lobo Margarita, Frejo María Teresa
Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain.
Department of Toxicology and Legal Medicine, Medical School, Complutense University of Madrid, 28041 Madrid, Spain.
Toxicology. 2016 Jun 15;361-362:1-11. doi: 10.1016/j.tox.2016.06.019. Epub 2016 Jul 1.
Cadmium is a toxic compound reported to produce cognitive dysfunctions, though the mechanisms involved are unknown. In a previous work we described how cadmium blocks cholinergic transmission and induces greater cell death in primary cholinergic neurons from the basal forebrain. It also induces cell death in SN56 cholinergic neurons from the basal forebrain through M1R blockage, alterations in the expression of AChE variants and GSK-3β, and an increase in Aβ and total and phosphorylated Tau protein levels. It was observed that the silencing or blockage of M1R altered ChAT activity, GSK-3β, AChE splice variants gene expression, and Aβ and Tau protein formation. Furthermore, AChE-S variants were associated with the same actions modulated by M1R. Accordingly, we hypothesized that cholinergic transmission blockage and higher sensitivity to cadmium-induced cell death of primary basal forebrain cholinergic neurons is mediated by M1R blockage, which triggers this effect through alteration of the expression of AChE variants. To prove this hypothesis, we evaluated, in primary culture from the basal forebrain region, whether M1R silencing induces greater cell death in cholinergic neurons than cadmium does, and whether in SN56 cells M1R mediates the mechanisms described so as to play a part in the cadmium induction of cholinergic transmission blockage and cell death in this cell line through alteration of the expression of AChE variants. Our results prove that M1R silencing by cadmium partially mediates the greater cell death observed on basal forebrain cholinergic neurons. Moreover, all previously described mechanisms for blocking cholinergic transmission and inducing cell death on SN56 cells after cadmium exposure are partially mediated by M1R through the alteration of AChE expression. Thus, our results may explain cognitive dysfunctions observed in cadmium toxicity.
镉是一种据报道会导致认知功能障碍的有毒化合物，但其涉及的机制尚不清楚。在之前的一项研究中，我们描述了镉如何阻断胆碱能传递，并在基底前脑的原代胆碱能神经元中诱导更多的细胞死亡。它还通过M1R阻断、AChE变体和GSK-3β表达的改变以及Aβ以及总Tau蛋白和磷酸化Tau蛋白水平的增加，诱导基底前脑的SN56胆碱能神经元发生细胞死亡。据观察，M1R的沉默或阻断会改变ChAT活性、GSK-3β、AChE剪接变体基因表达以及Aβ和Tau蛋白的形成。此外，AChE-S变体与M1R调节的相同作用相关。因此，我们推测，胆碱能传递的阻断以及基底前脑原代胆碱能神经元对镉诱导的细胞死亡的更高敏感性是由M1R阻断介导的，M1R通过改变AChE变体的表达触发这种效应。为了验证这一假设，我们在来自基底前脑区域的原代培养物中评估了M1R沉默是否比镉诱导胆碱能神经元发生更多的细胞死亡，以及在SN56细胞中M1R是否介导上述机制，从而通过改变AChE变体的表达在该细胞系中参与镉诱导的胆碱能传递阻断和细胞死亡。我们的结果证明，镉诱导的M1R沉默部分介导了在基底前脑胆碱能神经元中观察到的更多细胞死亡。此外，镉暴露后在SN56细胞中所有先前描述的阻断胆碱能传递和诱导细胞死亡的机制均部分由M1R通过AChE表达的改变介导。因此，我们的结果可能解释了在镉毒性中观察到的认知功能障碍。
