| Epidemiologically,there is a positive correlation between Alzheimer’s disease(AD)and type 2 diabetes mellitus(T2DM),both of which have similar physiological mechanisms.As a result,more and more diabetes drugs are being used in Alzheimer’s disease research.Exendin-4 is a glucagon-like peptide-1(GLP-1)receptor agonist approved for the treatment of T2 DM.EXD is an analog based on the central helix design of Exendin-4.We investigated for the first time the neuroprotective effects of Exendin-4 and its structural mimic EXD in an Alzheimer’s disease model using transgenic C.elegans.In this study,the short-term and long-term toxicity of Exendin-4 and EXD to nematodes was evaluated.It was found that 1.2 mg/m L Exendin-4 could increase the motility of N2 by 20.22 % and decrease the concentration of lipofuscin in intestinal tract by 27.23 %,without affecting the growth and development of nematodes.In addition,1.2 mg/m L EXD can increase the locomotor capacity of N2 by 21.17 % and decrease the accumulation of lipofuscin in intestinal tract by 43.33 %.It was found that Exendin-4 and EXD mediated oxidative stress through the DAF-16/FOXO pathway,and the amount of DAF-16 transferred from cytoplasm to nucleus was dose-dependent.Superoxide dismutase(SOD-3),as a downstream molecule regulated by DAF-16/FOXO,is up-regulated in mRNA,activity and content.As another downstream molecule regulated by DAF-16/FOXO,the expression level of heat shock protein HSP-16.2 also gradually increased,thus reducing the paralysis of nematodes and ROS accumulation caused by Aβ1-42 protein accumulation in vivo,and also decreasing the mRNA level of Aβ1-42.The amount of genes related to insulin signaling pathway was proportional to the drug concentration.EXD was significantly higher than Exendin-4 in reducing the accumulation of lipofuscin,improving motility,promoting subcellular localization of DAF-16,reducing the accumulation of Aβ1-42 and enhancing antioxidant stress.In the future,EXD will be further modified in order to transform polypeptide drugs into small molecule compounds to fill the market vacancy of Alzheimer’s disease drugs. |
