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 agon-
ist exendin-4 (Ex-4) reduces tau hyperphosphorylation in T2D animals through upregulating in-
sulin 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 cultiva-
tion, and the number of insulin-positive cells as well as the expression levels of insulin synthesis-re-
lated genes were examined. The db/db mice were treated with a peripheral injection of Ex-4 and/or
intracerebroventricular (ICV) injection of siRNA to inhibit the expression of insulin synthesis-relat-
ed 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 in-
duced 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 in-
sulin levels which activated brain insulin signaling and subsequently alleviated tau hyperphosphory-
lation. However, when siRNA-neurod1 was injected to block insulin synthesis, the cognitive func-
tion of db/db mice was not improved under the action of Ex-4 anymore. Moreover, the brain in-
sulin levels dropped to an extremely low level, and the phosphorylation level of tau increased signi-
ficantly.
Conclusion:
This study demonstrated that Ex-4 improved cognition function by promoting brain in-
sulin synthesis followed by the activation of brain insulin signaling and alleviation of tau hyper-
phosphorylation.
Brain Insulin Signaling, Alzheimer Disease Pathology, and Cognitive Function