Effect And Mechanism Of Imidazole On Transgenic Drosophila Model By Blocking The Aβ Ion Channel

Alzheimer’s disease（AD）attracts most attention since the first time it was definited.Along with the development of science and research,one of the neuro-pathomechanism could be characterized by accumulation and aggregation of Aβ.Aβwith different forms show diversity of pathological toxicity through the progression of AD.Lots of hypotheses have been proposed about Aβneurotoxicity including oxidative stress,mitochondria dysfunction,and especially the mis-regulation of intracellular calcium.The formation of Aβtrans-membrane channel is a break-through point for AD treatment.Owing to the interaction between Aβand neuronal cell membrane,the intracellular calcium concentration increases,that affects the imbalance of the calcium homeostasis and further the neurotoxicity.The Aβchannel hypothesis is proposed that the hydrophilic N-terminus third（residues 1-14,S1）of amyloid peptide composes the lining of the Aβchannel’s pore,which encompasses the His¹³-His¹⁴ diad around the axis.The channel is electronegative,characterized by its selective affinity with cations including Ca²⁺.Imidazole（IMI）especially the imidazole ring was supposed binding to the side chains of Aβpeptides.In this study Gal4/UAS system is adopted on targeted expression of human Aβ42 in flies to explore the imidazole interaction with the counterpart and study its effect in vivo and in vitro.The results demonstrate that Imidazole could not only remedy the learning memory defect in AD drosophila model induced by Aβ42,but also inhibite the activation of JNK signaling by regulating the level of phosphorylation.Furthermore,freshly-prepared oligomeric Aβ42 peptide ascended primary pupal neuronal calcium concentration and this phenomenon was alleviated by IMI and Zn²⁺.These findings suggest inhibitors of the Aβchannel maybe a new target for discovering drugs against AD.