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Current Alzheimer Research

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ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

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Research Article

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

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*

Volume 18, Issue 7, 2021

Published on: 29 September, 2021

Page: [546 - 557] Pages: 12

DOI: 10.2174/1567205018666210929150004

Price: $65

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.

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