Article Text

Exendin-4, a Glucagon-Like Peptide-1 Receptor Agonist, Reduces Alzheimer Disease-Associated Tau Hyperphosphorylation in the Hippocampus of Rats With Type 2 Diabetes
  1. Weijie Xu, MD,
  2. Yan Yang, MD, PhD,
  3. Gang Yuan, MD, PhD,
  4. Wenjun Zhu, BS,
  5. Delin Ma, MD,
  6. Shuhong Hu, MD, PhD
  1. From the Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  1. Received July 11, 2014, and in revised form October 28, 2014.
  2. Accepted for publication October 31, 2014.
  3. Reprints: Shuhong Hu, MD, PhD, Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei 430030, China. E-mail: hushuhong06{at}
  4. Supported by the Natural Science Foundation of China (81100582 to Y.Y., 81370941 to G.Y.), China International Medical Foundation–Novo Nordisk China Diabetes Young Scientific Talent Research Funding (2014), and the Frontier Exploration Funding of Huazhong University of Science and Technology (2014TS071).
  5. W.X., Y.Y., and G.Y. contributed to experimental design and execution, data analysis, and article writing. W.Z., D.M., and T.J. contributed to experimental execution; W.X. contributed to data analysis. W.X. and S.H. contributed to the overall research design, data analysis and interpretation, and article writing. All authors read and approved the final study.
  6. The authors have no conflict of interest to declare.


Background Impaired insulin signaling pathway in the brain in type 2 diabetes (T2D) is a risk factor for Alzheimer disease (AD). Glucagon-like peptide-1 (GLP-1) and its receptor agonist are widely used for treatment of T2D. Here we studied whether the effects of exendin-4 (EX-4), a long-lasting GLP-1 receptor agonist, could reduce the risk of AD in T2D.

Materials and Methods Type 2 diabetes rats were injected with EX-4 for 28 consecutive days. Blood glucose and insulin levels, as well as GLP-1 and insulin in cerebrospinal fluid, were determined during the experiment. The phosphorylation level of tau at individual phosphorylation sites, the activities of phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT), and glycogen synthase kinase-3β (GSK-3β) were analyzed with Western blots.

Results The levels of phosphorylated tau protein at site Ser199/202 and Thr217 level in the hippocampus of T2D rats were found to be raised notably and evidently decreased after EX-4 intervention. In addition, brain insulin signaling pathway was ameliorated after EX-4 treatment, and this result was reflected by a decreased activity of PI3K/AKT and an increased activity of GSK-3β in the hippocampus of T2D rats as well as a rise in PI3K/AKT activity and a decline in GSK-3β activity after 4 weeks intervention of EX-4.

Conclusions These results demonstrate that multiple days with EX-4 appears to prevent the hyperphosphorylation of AD-associated tau protein due to increased insulin signaling pathway in the brain. These findings support the potential use of GLP-1 for the prevention and treatment of AD in individuals with T2D.

Key Words
  • type 2 diabetes
  • Alzheimer disease
  • glucagon-like peptide-1 receptor agonist
  • insulin signaling pathway
  • tau protein

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