Department of Toxicology and Legal Medicine, Medical School, Complutense University of Madrid, 28041, Madrid, Spain.
Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, 28040, Madrid, Spain.
Food Chem Toxicol. 2018 Nov;121:297-308. doi: 10.1016/j.fct.2018.09.016. Epub 2018 Sep 11.
Cadmium, a neurotoxic environmental compound, produces cognitive disorders, although the mechanism remains unknown. Cadmium induces a more pronounced cell death on cholinergic neurons from basal forebrain (BF), mediated, in part, by increase in Aβ and total and phosphorylated Tau protein levels, which may explain cadmium effects on learning and memory processes. Cadmium downregulates the expression of heat shock proteins (HSPs) HSP 90, HSP70 and HSP27, and of HSF1, the master regulator of the HSP pathway. HSPs proteins reduce the production of Aβ and phosphorylated Tau proteins and avoid cell death pathways induction. Thus, we hypothesized that cadmium induced the production of Aβ and Tau proteins by HSP pathway disruption through HSF1 expression alteration, leading to BF cholinergic neurons cell death. Our results show that cadmium downregulates HSF1, leading to HSP90, HSP70 and HSP27 gene expression downregulation in BF SN56 cholinergic neurons. In addition, cadmium induced Aβ and total and phosphorylated Tau proteins generation, mediated partially by HSP90, HSP70 and HSP27 disruption, leading to cell death. These results provide new understanding of the mechanisms contributing to cadmium harmful effects on cholinergic neurons.
镉是一种神经毒性的环境化合物，可导致认知障碍，但其作用机制尚不清楚。镉可诱导基底前脑（BF）中的胆碱能神经元发生更明显的细胞死亡，部分是通过增加 Aβ 和总 Tau 蛋白及磷酸化 Tau 蛋白水平介导的，这可能解释了镉对学习和记忆过程的影响。镉下调热休克蛋白（HSPs）HSP90、HSP70 和 HSP27 的表达，以及 HSP 途径的主要调节因子 HSF1。HSPs 蛋白减少 Aβ 和磷酸化 Tau 蛋白的产生，并避免细胞死亡途径的诱导。因此，我们假设镉通过 HSF1 表达改变破坏 HSP 途径，导致 Aβ 和 Tau 蛋白的产生，从而导致 BF 胆碱能神经元死亡。我们的结果表明，镉下调 HSF1，导致 BF SN56 胆碱能神经元中 HSP90、HSP70 和 HSP27 基因表达下调。此外，镉诱导 Aβ 和总 Tau 蛋白及磷酸化 Tau 蛋白的产生，部分是通过 HSP90、HSP70 和 HSP27 的破坏介导的，导致细胞死亡。这些结果为理解镉对胆碱能神经元的有害影响的机制提供了新的认识。
