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Neuroscience. 2014 Sep 26;277:6-13. doi: 10.1016/j.neuroscience.2014.02.022. Epub 2014 Feb 27.

Lixisenatide rescues spatial memory and synaptic plasticity from amyloid β protein-induced impairments in rats.

Author information

1
Department of Physiology, Shanxi Medical University, Taiyuan 030001, China.
2
Division of Biomed and Life Sciences, Faculty of Health and Medicine Lancaster University, Lancaster LA1 4YQ, UK.
3
Second Affiliated Hospital of Shanxi Medical University, Taiyuan 030001, China.
4
Department of Pathology, Shanxi Medical University, Taiyuan 030001, China.
5
Department of Physiology, Shanxi Medical University, Taiyuan 030001, China. Electronic address: jinshunqi2006@yahoo.com.

Abstract

Alzheimer's disease (AD) is a progressive and degenerative disorder accompanied by cognitive impairment, but effective strategies against AD are currently not available. Interestingly, glucagon-like peptide-1 (GLP-1) used in type 2 diabetes mellitus (T2DM) has shown neuroprotective effects in preclinical studies of AD. Lixisenatide, an effective GLP-1 receptor (GLP-1R) agonist with much longer half life than GLP-1, has been licensed in the EU as a treatment for T2DM. However, the neuroprotective effects of lixisenatide in the brain remain to be clarified. In the present study, we report for the first time the effects of lixisenatide on the amyloid β (Aβ) protein-induced impairments in spatial learning and memory of rats, and investigated its electrophysiological and molecular mechanisms. We found that: (1) bilateral intrahippocampal injection of Aβ25-35 resulted in a significant decline in spatial learning and memory of rats, as well as a suppression of in vivo hippocampal long-term potentiation (LTP); (2) lixisenatide treatment effectively prevented the Aβ25-35-induced impairments; (3) lixisenatide inhibited the Aβ25-35 injection-induced activation of glycogen synthase kinase 3β (GSK3β), with a significant increase in the phosphorylation of ser9 and a significant decrease in the phosphorylation of Y216. These results indicate that lixisenatide, by affecting the PI3K-Akt-GSK3β pathway, can prevent Aβ-related impairments in synaptic plasticity and spatial memory of rats, suggesting that lixisenatide may be a novel and effective treatment for AD.

KEYWORDS:

Alzheimer’s disease; Morris water maze; amyloid β-protein; glycogen synthase kinase 3β; lixisenatide; long-term potentiation

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