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Exendin-4 Improves Cognitive Function of Diabetic Mice via Increasing Brain Insulin Synthesis

[ Vol. 18 , Issue. 7 ]

Author(s):

Xuemin Peng, Xiaoli Shi, Jiaojiao Huang, Shujun Zhang, Yongli Yan, Delin Ma, Weijie Xu, Weijie Xu, Kun Dong, Jing Tao, Mengni Li and Yan Yang*   Pages 546 - 557 ( 12 )

Abstract:


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-3β 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.

Keywords:

Type 2 diabetes, Alzheimer's disease, glucagon-like peptide-1, insulin, exendin-4, db/db.

Affiliation:

Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei



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