George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, USA.
Interdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI, USA.
Neurotoxicology. 2017 Sep;62:218-223. doi: 10.1016/j.neuro.2017.07.029. Epub 2017 Jul 29.
The presence of fibrillary lesions, which are mainly composed of the microtubule associated protein tau (MAPT) in neurons, has gained immense recognition due to their presence in numerous neurodegenerative diseases, including Alzheimer's disease (AD). Dysregulation of tau is related with its altered site-specific phosphorylation which is followed by tau polymerization, neuronal dysfunction and death. Previous reports by us suggest that molecular alterations favor abundant tau phosphorylation and immunoreactivity in the frontal cortex of aged primates and rodents with past exposure to lead (Pb). Here we report the involvement of Pb-induced alterations in tau and hyperphosphorylation of tau in differentiated Human Neuroblastoma SH-SY5Y cells exposed to a series of Pb concentrations (5-100μM) for 48h. These cells were analyzed for the protein expression of total tau, site-specific tau hyperphosphorylation, cyclin dependent kinase 5 (CDK5) and p35/p25 at selected time points (24-144h), after Pb exposure had ceased. Western blot analysis revealed aberrant tau levels as well as site-specific tau hyperphosphorylation accompanied by elevated CDK5 levels and altered protein ratio of p35/p25 particularly at 72 and 144h. These changes provide additional evidence that neurodegenerative events are subject to environmental influences.
由于其在包括阿尔茨海默病（AD）在内的许多神经退行性疾病中的存在，纤维状病变（主要由神经元中的微管相关蛋白 tau（MAPT）组成）得到了广泛的认可。tau 的失调与其特定部位磷酸化的改变有关，随后是 tau 聚合、神经元功能障碍和死亡。我们之前的报告表明，分子改变有利于过去接触过铅（Pb）的老年灵长类动物和啮齿动物的额皮质中丰富的 tau 磷酸化和免疫反应性。在这里，我们报告了在分化的人神经母细胞瘤 SH-SY5Y 细胞中，Pb 诱导的 tau 改变和 tau 的过度磷酸化的参与，这些细胞在停止 Pb 暴露后，暴露于一系列 Pb 浓度（5-100μM）48h。在 Pb 暴露后的选定时间点（24-144h），对这些细胞进行总 tau、tau 特定部位过度磷酸化、细胞周期蛋白依赖性激酶 5（CDK5）和 p35/p25 的蛋白表达进行了分析。Western blot 分析显示异常的 tau 水平以及伴随的 tau 特定部位过度磷酸化，同时 CDK5 水平升高和 p35/p25 的蛋白比例改变，特别是在 72 和 144h。这些变化提供了更多证据表明神经退行性事件受到环境影响。
