1731-P: The Mechanism of the Protective Effect of GLP-1 on the Amelioration of Alzheimer’s Disease by Enhancing Brain Insulin Production

Background: Growing evidence supported that type 2 diabetes mellitus (T2DM) patients had a greater risk of developing Alzheimer’s disease (AD). Insulin secreted by “β cells” in brain played a critical role in T2DM patients and in AD patients. GLP-1 could improve cognition in AD patients via enhancing brain insulin signaling. We hypothesize the therapeutic effect of GLP-1 in T2DM might be due to promoting the insulin secretion of “β cells” in the nervous system. However, the molecular mechanism is unclear. Methods: The hippocampus cell- HT-22 cell line and T2DM rats were used in this study. The genes of insulin syntheses, animals’ cognitive function and the phosphorylation of tau protein in hippocampus of T2DM brain were examined. Results: Firstly, HT22 cell line was intervened by GLP-1 or high glucose or GLP-1+ high glucose. When stimulated by GLP-1 combined with high glucose, IRS1/PI3K/AKT located in insulin signal pathway could be activated and the expression of neurod-1 and ngn3 (insulin synthesis genes) were notably increased. These results indicated that neuronal cell could secrete insulin under a certain condition. Secondly, RAAV-sh- neurod-1 and RAAV-sh-ngn3 were icv to the T2DM rats to prevent the production of brain insulin. The Barnes Maze test indicated the T2DM rats with peripheral GLP-1 and icv RAAV-sh-nc injection had a more intelligence than those with peripheral GLP-1 and icv RAAV-sh- neurod-1 and RAAV-sh-ngn3. Thirdly, the T2DM rats with peripheral GLP-1 and icv RAAV-sh- neurod-1 and RAAV-sh-ngn3 had a significantly hyperphsphorylation of tau protein than those rats with peripheral GLP-1 and icv RAAV-sh-nc injection. This result showed that brain insulin could improve cognition by GLP-1 in T2DM rats. Conclusions: These results suggested that neuronal cells might synthesis and secrete insulin under the condition of high glucose and GLP-1. And GLP-1 could not improve cognitive ability in T2DM when brain insulin synthesized was prevented. Disclosure J. Huang: None. Y. Yang: None. Funding National Natural Science Foundation of China (81670754)