Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran.
Department of Biology, Faculty of Basic Sciences, University of Zabol, Zabol, Iran.
Arch Gerontol Geriatr. 2021 May-Jun;94:104355. doi: 10.1016/j.archger.2021.104355. Epub 2021 Jan 25.
Two major pathological hallmarks of Alzheimer's disease (AD) are amyloid plaques and neurofibrillary tangles of hyperphosphorylated tau. Aggregation of amyloid-β (Aβ) is considered as the primary insult in AD. However, failure in treatments based on targetingAβ without considering the pathologic tau and close correlation between pathological tau and cognitive decline highlighted the crucial role of tau in AD. Loss of synaptic plasticity and cognitive decline, partly due to decrease in Brain Derived Neurotrophic Factor (BDNF), are other hallmarks of AD. Aβ and tau downregulate BDNF at both transcriptional and translational levels. The aim of this research was to study the expression levels of Drosophila Neuroteophin 1 (DNT1), as an orthologue of BDNF, in flies expressing Aβ or tau. Levels of DNT1 were determined using quantitative real time PCR. Behavioral and Biochemical investigations were also performed in parallel. Our results showed that there is a significant decrease in the levels of DNT1 expression in Aβ or tau expressing flies. Interestingly, a significant increase was observed in sensitivity to ethanol in both transgenic flies. Rise in Reactive Oxygen Species (ROS) levels was also detected. We concluded that both Aβ and pathological tau exert their toxic effect on DNT1 expression, ROS production, and response to ethanol, independently. Interestingly, pathological tau showed higher impact on the ROS production compared to Aβ. It seems that Aβ and tau transgenic flies are proper models to investigate the interplay between BDNF and oxidative stress, and also to assess the mechanism underlying behavioral response to ethanol.
阿尔茨海默病（AD）的两个主要病理学特征是淀粉样斑块和过度磷酸化 tau 的神经原纤维缠结。淀粉样-β（Aβ）的聚集被认为是 AD 的主要损伤。然而，基于靶向 Aβ 的治疗方法失败，而没有考虑病理性 tau 以及病理性 tau 与认知能力下降之间的密切相关性，突显了 tau 在 AD 中的关键作用。突触可塑性丧失和认知能力下降，部分是由于脑源性神经营养因子（BDNF）的减少，是 AD 的另一个特征。Aβ 和 tau 在转录和翻译水平下调 BDNF。本研究的目的是研究表达 Aβ 或 tau 的果蝇中果蝇神经生长因子 1（DNT1）作为 BDNF 的同源物的表达水平。使用定量实时 PCR 确定 DNT1 的水平。同时进行行为和生化研究。我们的结果表明，在表达 Aβ 或 tau 的果蝇中，DNT1 表达水平显著降低。有趣的是，在两种转基因果蝇中均观察到对乙醇的敏感性显著增加。还检测到活性氧（ROS）水平的升高。我们得出结论，Aβ 和病理性 tau 独立地对 DNT1 表达、ROS 产生和对乙醇的反应产生毒性作用。有趣的是，病理性 tau 对 ROS 产生的影响高于 Aβ。似乎 Aβ 和 tau 转基因果蝇是研究 BDNF 和氧化应激相互作用以及评估对乙醇的行为反应机制的合适模型。
