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首页> 外文期刊>IBRO Reports >Presence of insoluble Tau following rotenone exposure ameliorates basic pathways associated with neurodegeneration
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Presence of insoluble Tau following rotenone exposure ameliorates basic pathways associated with neurodegeneration

机译：鱼藤酮暴露后存在不溶性Tau改善了与神经变性相关的基本途径

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Protein aggregation is an important feature of neurodegenerative disorders. In Alzheimer's disease (AD) protein aggregates are composed of hyperphosphorylated Tau and amyloid beta peptide (Aβ). Despite the involvement and identification of the molecular composition of these aggregates, their role in AD pathophysiology is not fully understood. However, depositions of these insoluble aggregates are typically reported as pathogenic and toxic for cell homeostasis. New evidences suggest that the deposition of these aggregates is a protective mechanism that preserves cell from toxic insults associated with the early stages of neurodegenerative diseases. To better understand the biological role of the protein aggregation with regard its effects in cellular homeostasis, the present study investigated the role of insoluble Tau and Tau aggregates on crucial cellular parameters such as redox homeostasis, proteasome activity and autophagy in hippocampal cell cultures and hippocampus of aged Lewis rats using a rotenone-induced aggregation model. Neurons were exposed to rotenone in different concentrations and exposure times aiming to determine the interval required for Tau aggregation. Our experimental design allowed us to demonstrate that rotenone exposure induces Tau hyperphosphorylation and aggregation in a concentration and time-dependent manner. Oxidative stress triggered by rotenone exposure was observed with the absence of Tau aggregates and was reduced or absent when Tau aggregates were present. This reduction of oxidative stress along with the presence of insoluble Tau was independent of alterations in antioxidant enzymes activities or cell death. In addition, rotenone induced oxidative stress was mainly associated with decrease in proteasome activity and autophagy flux. Conversely, when insoluble Tau appeared, autophagy turns to be overactivated while proteasome activity remained low. Our studies significantly advance the understanding that Tau aggregation might exert protective cellular effects, at least briefly, when neurons are facing neurodegeneration stimulus. We believe that our data add more complexity for the understanding of protein aggregation role in AD etiology. Graphical abstract Display Omitted Highlights ? Rotenone triggers Tau hyperphosphorylation and aggregation in a time and concentration-dependent manner, being the temporal component predominant. ? Autophagy is modulated differently before and during Tau aggregation, while proteasome activity is reduced in both conditions. ? The formation of Tau aggregates normalizes cellular dysfunctions detected in the absence of them.
机译：蛋白质聚集是神经退行性疾病的重要特征。在阿尔茨海默氏病（AD）中，蛋白质聚集体由高磷酸化的Tau和淀粉样β肽（Aβ）组成。尽管涉及并鉴定了这些聚集体的分子组成，但是它们在AD病理生理学中的作用还没有被完全理解。然而，这些不溶性聚集体的沉积通常被报告为细胞稳态的致病性和毒性。新的证据表明，这些聚集体的沉积是一种保护机制，可以使细胞免受与神经退行性疾病早期相关的毒性伤害。为了更好地了解蛋白质聚集体在细胞稳态中的生物学作用，本研究调查了不溶性Tau和Tau聚集体在海马细胞培养物和海马中重要的细胞参数如氧化还原稳态，蛋白酶体活性和自噬中的作用。使用鱼藤酮诱导的聚集模型老化Lewis大鼠。将神经元暴露于不同浓度和暴露时间的鱼藤酮中，旨在确定Tau聚集所需的间隔。我们的实验设计使我们能够证明鱼藤酮的暴露以浓度和时间依赖性方式诱导Tau过度磷酸化和聚集。在没有Tau聚集体的情况下，观察到鱼藤酮暴露引发的氧化应激，当存在Tau聚集体时，氧化应激会降低或不存在。氧化应激的减少以及不溶性Tau的存在与抗氧化酶活性或细胞死亡的改变无关。此外，鱼藤酮诱导的氧化应激主要与蛋白酶体活性和自噬通量的降低有关。相反，当不溶的Tau出现时，自噬转为过度活化，而蛋白酶体的活性仍然很低。我们的研究极大地推动了人们的认识，即当神经元面临神经退行性刺激时，Tau聚集至少可以短暂地发挥保护性细胞作用。我们认为，我们的数据为理解AD病因中的蛋白质聚集作用增加了更多的复杂性。图形摘要显示省略的突出显示？鱼藤酮以时间和浓度依赖性的方式触发Tau过度磷酸化和聚集，这是时间上的主要成分。 ？在Tau聚集之前和期间，自噬的调节方式有所不同，而两种情况下蛋白酶体的活性均降低。 ？ Tau聚集体的形成可正常化在不存在Tau聚集体时检测到的细胞功能障碍。

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