期刊
NEUROSCIENCE
卷 277, 期 -, 页码 6-13出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuroscience.2014.02.022
关键词
lixisenatide; amyloid beta-protein; Morris water maze; long-term potentiation; glycogen synthase kinase 3 beta; Alzheimer's disease
资金
- National Science Foundation of China [31271201]
- Special Foundation for High Schools Doctoral Program of Ministry of Education [20101417110001]
- Natural Science Foundation of Shanxi Province of China [2010-51]
- Youth Foundation of Shanxi Medical University [057483]
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 beta (A beta) 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 A beta 25-35 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 A beta 25-35-induced impairments; (3) lixisenatide inhibited the A beta 25-35 injection-induced activation of glycogen synthase kinase 3 beta (GSK3 beta), 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-GSK3 beta pathway, can prevent A beta-related impairments in synaptic plasticity and spatial memory of rats, suggesting that lixisenatide may be a novel and effective treatment for AD. (C) 2014 Published by Elsevier Ltd. on behalf of IBRO.
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