DNT1 Downregulation and Increased Ethanol Sensitivity in Transgenic Drosophila Models of Alzheimer's Disease

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 Aβ₄₂ or tau^R406W. 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 Aβ₄₂ or tau^R406W 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 Aβ₄₂ and tau^R406W 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.