Title:Exendin-4 Improves Cognitive Function of Diabetic Mice via Increasing Brain Insulin Synthesis
Volume: 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*
Affiliation:
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei,China
Keywords:
Type 2 diabetes, Alzheimer's disease, glucagon-like peptide-1, insulin, exendin-4, db/db.
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.
