PMID- 34587885 OWN - NLM STAT- MEDLINE DCOM- 20220401 LR - 20220401 IS - 1875-5828 (Electronic) IS - 1567-2050 (Linking) VI - 18 IP - 7 DP - 2021 TI - Exendin-4 Improves Cognitive Function of Diabetic Mice via Increasing Brain Insulin Synthesis. PG - 546-557 LID - 10.2174/1567205018666210929150004 [doi] AB - BACKGROUND AND OBJECTIVE: Type 2 Diabetes (T2D) patients are more prone to develop Alzheimer's Disease (AD). We have previously shown that Glucagon-like peptide-1 receptor agonist exendin-4 (Ex-4) reduces tau hyperphosphorylation in T2D animals through upregulating insulin signaling, and peripheral injected Ex-4 increases insulin levels in the T2D brain. This study aims to further clarify whether the elevated insulin in the brain is produced by nerve cells under the action of Ex-4. METHODS: The neuronal cell line-HT22 was treated with Ex-4 under high glucose or normal cultivation, and the number of insulin-positive cells as well as the expression levels of insulin synthesis-related genes were examined. The db/db mice were treated with the peripheral injection of Ex-4 and/or IntraCerebroVentricular (ICV) injection of siRNA to inhibit the expression of insulin synthesis- related genes and the behavior tests were carried on. Finally, plasma glucose, Cerebrospinal Fluid (CSF) glucose, CSF insulin, phosphorylation of tau, phosphorylation of AKT and GSK-3beta of db/db mice were detected. RESULTS: We found that Ex-4 promoted the expression of insulin synthesis-related genes and induced an obvious increase of insulin-positive HT-22 neuronal cells in a high glucose environment. Peripheral injection of Ex-4 improved the cognitive function of db/db mice and increased brain insulin levels which activated brain insulin signaling and subsequently alleviated tau hyperphosphorylation. However, when siRNA-neurod1 was injected to block insulin synthesis, the cognitive function of db/db mice was not improved under the action of Ex-4 anymore. Moreover, the brain insulin levels dropped to an extremely low level, and the phosphorylation level of tau increased significantly. CONCLUSION: This study demonstrated that Ex-4 improved cognition function by promoting brain insulin synthesis followed by the activation of brain insulin signaling and alleviation of tau hyperphosphorylation. CI - Copyright(c) Bentham Science Publishers; For any queries, please email at epub@benthamscience.net. FAU - Peng, Xuemin AU - Peng X AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Shi, Xiaoli AU - Shi X AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Huang, Jiaojiao AU - Huang J AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Zhang, Shujun AU - Zhang S AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Yan, Yongli AU - Yan Y AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Ma, Delin AU - Ma D AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Xu, Weijie AU - Xu W AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Xu, Weijie AU - Xu W AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Dong, Kun AU - Dong K AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Tao, Jing AU - Tao J AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Li, Mengni AU - Li M AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Yang, Yan AU - Yang Y AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. LA - eng GR - 81670754 , 81974114, 81800686, 81600661/National Natural Science Foundation of China/ GR - 2018076/China International Medical Foundation/ PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United Arab Emirates TA - Curr Alzheimer Res JT - Current Alzheimer research JID - 101208441 RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (tau Proteins) RN - 9P1872D4OL (Exenatide) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) SB - IM MH - Animals MH - Brain/metabolism MH - Cognition MH - *Diabetes Mellitus, Experimental/drug therapy MH - *Diabetes Mellitus, Type 2/metabolism MH - Exenatide/pharmacology MH - Glycogen Synthase Kinase 3 beta/metabolism MH - Hippocampus/metabolism MH - Humans MH - Hypoglycemic Agents/pharmacology MH - Insulin MH - Mice MH - Phosphorylation MH - tau Proteins/metabolism OTO - NOTNLM OT - Alzheimer's disease OT - Type 2 diabetes OT - db/db. OT - exendin-4 OT - glucagon-like peptide-1 OT - insulin EDAT- 2021/10/01 06:00 MHDA- 2022/04/02 06:00 CRDT- 2021/09/30 05:34 PHST- 2021/01/20 00:00 [received] PHST- 2021/06/16 00:00 [revised] PHST- 2021/08/24 00:00 [accepted] PHST- 2021/10/01 06:00 [pubmed] PHST- 2022/04/02 06:00 [medline] PHST- 2021/09/30 05:34 [entrez] AID - CAR-EPUB-118240 [pii] AID - 10.2174/1567205018666210929150004 [doi] PST - ppublish SO - Curr Alzheimer Res. 2021;18(7):546-557. doi: 10.2174/1567205018666210929150004.