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Amelioration of neurodegenerative changes in cellular and rat models of diabetes-related Alzheimer’s disease by exendin-4

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Abstract

Growing evidence suggests that type 2 diabetes mellitus (DM) is associated with age-dependent Alzheimer’s disease (AD), the latter of which has even been considered as type 3 diabetes. Several physiopathological features including hyperglycemia, oxidative stress, and dysfunctional insulin signaling relate DM to AD. In this study, high glucose-, oxidative stress-induced neuronal injury and intracerebroventricular-streptozotocin (ICV-STZ) animals as the possible models for diabetes-related AD were employed to investigate the effects of exendin-4 (Ex-4), a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, on diabetes-associated Alzheimer-like changes as well as the molecular mechanisms involved. Our study demonstrated that GLP-1/Ex-4 could exert a protective effect against reduced viability of PC12 cells caused by high glucose and that this protective effect was mediated via the PI3-kinase pathway. In addition, GLP-1/Ex-4 ameliorated oxidative stress-induced injury in PC12 cells. In rat models, bilateral ICV-STZ administration was used to produce impaired insulin signaling in the brain. Fourteen days following ICV-STZ injection, rats treated with twice-daily Ex-4 had better learning and memory performance in the Morris water maze test compared with rats treated with saline. Additionally, histopathological evaluation confirmed the protective effects of Ex-4 treatment on hippocampal neurons against degeneration. Furthermore, we demonstrated that Ex-4 reversed ICV-STZ-induced tau hyperphosphorylation through downregulation of GSK-3β activity, a key kinase in both DM and AD. Our findings suggests that Ex-4 can protect neurons from diabetes-associated glucose metabolic dysregulation insults in vitro and from ICV-STZ insult in vivo, and that Ex-4 may prove of therapeutic value in the treatment of AD especially DM-related AD.

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Acknowledgements

This work was co-financed by the National Natural Science Foundation (No. 30973667), the Jiangsu Provincial Research Innovation Program for College Graduates (CX10B-377Z), Qing Lan Project and the 111 Project (111-2-07).

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Authors and Affiliations

  1. State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, China

    Song Chen, Feng-mao An, Wen-bing Yao & Xiang-dong Gao

  2. Medical School, Southeast University, Nanjing, 210009, China

    Ai-ran Liu

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  1. Song Chen
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  2. Ai-ran Liu
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  3. Feng-mao An
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  4. Wen-bing Yao
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  5. Xiang-dong Gao
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Corresponding authors

Correspondence to Wen-bing Yao or Xiang-dong Gao.

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Song Chen and Ai-ran Liu contributed equally to this work.

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Chen, S., Liu, Ar., An, Fm. et al. Amelioration of neurodegenerative changes in cellular and rat models of diabetes-related Alzheimer’s disease by exendin-4. AGE 34, 1211–1224 (2012). https://doi.org/10.1007/s11357-011-9303-8

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  • DOI: https://doi.org/10.1007/s11357-011-9303-8

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