Abstract：
BACKGROUND: Tau, Amyloid-beta (Aβ42), and Glycogen synthase kinase 3 (GSK3) contribute to synaptic dysfunction observed in Alzheimer\'s disease (AD), the most common form of dementia. In the current study, the effect of pan-neuronal expression of TauWT, Aβ42, or shaggy (orthologue of GSK3) in Drosophila melanogaster was assessed on the locomotor function, ethanol sensitivity, synaptic genes and CREB expression. The effect of TauWT and Aβ42 on the expression of shaggy was also determined.
RESULTS: Gene expression analysis was performed using quantitative real-time RT-PCR method. While syt1, SNAP25 and CREB (upstream transcription factor of syt1 and SNAP25) were upregulated in flies expressing TauWT or Aβ42, a prominent decline was observed in those genes in shaggy expressing flies. Although all transgenic flies showed climbing disability and higher sensitivity to ethanol, abnormality in these features was significantly more prominent in transgenic flies expressing shaggy compared to TauWT or Aβ42. Despite a significant upregulation of shaggy transcription in TauWT expressing flies, Aβ42 transgenic flies witnessed no significant changes.
CONCLUSIONS: TauWT, Aβ42, and shaggy may affect synaptic plasticity through dysregulation of synaptic genes and CREB, independently. However shaggy has more detrimental effect on synaptic genes expression, locomotor ability and sensitivity to ethanol. It is important when it comes to drug discovery. It appears that CREB is a direct effector of changes in synaptic genes expression as they showed similar pattern of alteration and it is likely to be a part of compensatory mechanisms independent of the GSK3/CREB pathway in TauWT or Aβ42 expressing flies.
RESULTS: Gene expression analysis was performed using quantitative real-time RT-PCR method. While syt1, SNAP25 and CREB (upstream transcription factor of syt1 and SNAP25) were upregulated in flies expressing TauWT or Aβ42, a prominent decline was observed in those genes in shaggy expressing flies. Although all transgenic flies showed climbing disability and higher sensitivity to ethanol, abnormality in these features was significantly more prominent in transgenic flies expressing shaggy compared to TauWT or Aβ42. Despite a significant upregulation of shaggy transcription in TauWT expressing flies, Aβ42 transgenic flies witnessed no significant changes.
CONCLUSIONS: TauWT, Aβ42, and shaggy may affect synaptic plasticity through dysregulation of synaptic genes and CREB, independently. However shaggy has more detrimental effect on synaptic genes expression, locomotor ability and sensitivity to ethanol. It is important when it comes to drug discovery. It appears that CREB is a direct effector of changes in synaptic genes expression as they showed similar pattern of alteration and it is likely to be a part of compensatory mechanisms independent of the GSK3/CREB pathway in TauWT or Aβ42 expressing flies.
摘要：
背景：Tau，淀粉样蛋白-β(Aβ42),和糖原合成酶激酶3（GSK3）有助于在阿尔茨海默病（AD）中观察到的突触功能障碍，最常见的痴呆症。在目前的研究中,TauWT的泛神经元表达的影响，对果蝇的Aβ42或shaggy（GSK3的直系同源物）的运动功能进行了评估，乙醇敏感性，突触基因和CREB表达。还测定了TauWT和Aβ42对shaggy表达的影响。
结果：使用定量实时RT-PCR方法进行基因表达分析。虽然syt1，SNAP25和CREB（syt1和SNAP25的上游转录因子）在表达TauWT或Aβ42的果蝇中上调，但在表达毛茸茸的果蝇中观察到这些基因的显着下降。尽管所有转基因果蝇都表现出攀爬障碍和对乙醇的更高敏感性，与TauWT或Aβ42相比，在表达shaggy的转基因果蝇中，这些特征的异常显着更为突出。尽管表达TauWT的果蝇中shaggy转录的显着上调，Aβ42转基因果蝇没有明显变化。
结论：TauWT，Aβ42和shaggy可能通过突触基因和CREB的失调影响突触可塑性，独立。然而，shaggy对突触基因表达有更有害的影响，运动能力和对乙醇的敏感性。在药物发现方面很重要。似乎CREB是突触基因表达变化的直接效应物，因为它们显示出相似的变化模式，并且很可能是补偿机制的一部分，而与TauWT或Aβ42表达果蝇的GSK3/CREB途径无关。
结果：使用定量实时RT-PCR方法进行基因表达分析。虽然syt1，SNAP25和CREB（syt1和SNAP25的上游转录因子）在表达TauWT或Aβ42的果蝇中上调，但在表达毛茸茸的果蝇中观察到这些基因的显着下降。尽管所有转基因果蝇都表现出攀爬障碍和对乙醇的更高敏感性，与TauWT或Aβ42相比，在表达shaggy的转基因果蝇中，这些特征的异常显着更为突出。尽管表达TauWT的果蝇中shaggy转录的显着上调，Aβ42转基因果蝇没有明显变化。
结论：TauWT，Aβ42和shaggy可能通过突触基因和CREB的失调影响突触可塑性，独立。然而，shaggy对突触基因表达有更有害的影响，运动能力和对乙醇的敏感性。在药物发现方面很重要。似乎CREB是突触基因表达变化的直接效应物，因为它们显示出相似的变化模式，并且很可能是补偿机制的一部分，而与TauWT或Aβ42表达果蝇的GSK3/CREB途径无关。
