P1‐181: DULAGLUTIDE IMPROVES LEARNING AND MEMORY IMPAIRMENT, HYPERPHOSPHORYLATED TAU AND NEUROFILAMENTS IN THE APP/PS1/TAU TRIPLE TRANSGENIC MICE

Impaired glucose uptake/utilization and impaired insulin signaling are the metabolic features of type 2 diabetes mellitus (T2DM) and Alzheimer's Disease (AD). Some studies proposed that AD is type 3 diabetes. Dulaglutide, a novel weekly administered long-acting glucagon-like peptide 1 (GLP-1) receptor agonist, is an incretin mimetic approved for type 2 diabetes mellitus treatment. Although studies also demonstrated other GLP-1receptor agonists (e.g. Exendin-4) have neurotrophic/protective activity in cellular and animal models of stroke, Alzheimer's and Parkinson's diseases, it's the first time to observe effects of dulaglutide on the treatment of AD in the world. The study is to explore the protective effects and mechanism of dulaglutide on the learning and memory impairment induced by STZ intraventricular injection in non-transgenic mice. The male 13 weeks icv-STZ C57BL6 mice were divided into four groups (n=5 each group) administrated by dulaglutide with or without GLP-1 receptor inhibitor Exenatide 9-39 (Ex9-39) for 4 weeks: (A) treated with saline; (B) dulaglutide (0.24mg/kg/w,ip.); (C) dulaglutide and Ex9-39; wild icv-saline C57BL6 mice served as blank control. Western blotting was used to detect the levels of phosphorylated Tau, neurofilaments (NFs) protein, phosphorylated PI3K/Akt/GSK-3β signaling pathway. ELISA was used to detect the effects of the deposit of Aβ42. Morris water maze (MWM) was assessed the spatial learning and memory ability. The weekly intraperitoneal injection of dulaglutide decreased the high levels of hyperphosphorylated tau and NFs in STZ mice, and improved the phosphorylation of PI3K/Akt/GSK-3β signaling pathway. Dulaglutide also significantly decreased the deposit of Aβ42 of STZ mice, shortening the escape latency and increasing the number of hidden platform crossings in MWM task, whereas dulaglutide did not significantly affect the body weight and fasting blood glucose in mice. The effects of dulaglutide on decreasing the hyperphosphorylation of tau and neurofilaments proteins through improving the PI3K/Akt/GSK-3β signaling pathway, and reducing level of Aβ42 may be related to its protective effects on impairment of AD-like learning and memory.