Differential dysregulation of CREB and synaptic genes in transgenic Drosophila melanogaster expressing shaggy (GSK3), TauWT, or Amyloid-beta

Abstract

Background: Tau, Amyloid-beta (Aβ 42 ), 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 Tau WT , Aβ 42 , or shaggy (orthologue of GSK3) in Drosophila melanogaster was assessed on the locomotor function, ethanol sensitivity, synaptic genes and CREB expression. The effect of Tau WT and Aβ 42 on the expression of shaggy was also determined.Methods and results: Gene expression analysis performed using quantitative real-time RT-PCR method.While syt1, SNAP25 and CREB (upstream transcription factor of syt1 and SNAP25) were upregulated in ies expressing TauWT or Aβ42, a prominent decline was observed in those genes in shaggy expressing ies. While all transgenic ies showed climbing disability and higher sensitivity to ethanol, abnormality in these features was signi cantly more prominent in transgenic ies expressing shaggy compared to TauWT or Aβ42. Despite a signi cant upregulation of shaggy transcription in TauWT expressing ies, Aβ42 transgenic ies witnessed no signi cant changes.Conclusions: Tau WT , Aβ 42 , 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 due to the same pattern of their alteration and it is likely to be a part of compensatory mechanisms independent of the GSK3/CREB pathway in Tau WT or Aβ 42 expressing ies.

Seed-Induced Accumulation of β-Amyloid Exacerbates Oxidative Stress in Drosophila

“…This conclusion is consistent with many previous studies. For example, the study from Fatemeh Ataellahi et al on transgenic Aβ42 and Tau drosophila showed that AD drosophila (transgenic Aβ42 and Tau) had a significant decline in the ability to climb a wall compared with the control group [9]. This study provided evidence about Aβ42 seeding mechanisms with a promising and time-saving model.…”