title: Lixisenatide rescues spatial memory and synaptic plasticity from amyloid β protein-induced impairments in rats.
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.
authors.affiliation: Department of Physiology, Shanxi Medical University, Taiyuan 030001, China.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Cai
authors.affiliation: Division of Biomed and Life Sciences, Faculty of Health and Medicine Lancaster University, Lancaster LA1 4YQ, UK.
authors.forename: C
authors.initials: C
authors.lastname: Hölscher
authors.affiliation: Department of Physiology, Shanxi Medical University, Taiyuan 030001, China.
authors.forename: X-H
authors.initials: XH
authors.lastname: Yue
authors.affiliation: Second Affiliated Hospital of Shanxi Medical University, Taiyuan 030001, China.
authors.forename: S-X
authors.initials: SX
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Shanxi Medical University, Taiyuan 030001, China.
authors.forename: X-H
authors.initials: XH
authors.lastname: Wang
authors.affiliation: Department of Physiology, Shanxi Medical University, Taiyuan 030001, China.
authors.forename: F
authors.initials: F
authors.lastname: Qiao
authors.affiliation: Department of Physiology, Shanxi Medical University, Taiyuan 030001, China.
authors.forename: W
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Physiology, Shanxi Medical University, Taiyuan 030001, China. Electronic address: jinshunqi2006@yahoo.com.
authors.forename: J-S
authors.initials: JS
authors.lastname: Qi
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D000067757:Glucagon-Like Peptide-1 Receptor; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy* / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000819:agonists / Q000378:metabolism; D065852:Spatial Memory / Q000187:drug effects* / Q000502:physiology; D000067758:Glucagon-Like Peptide-2 Receptor
chemical_list: D016229:Amyloid beta-Peptides; D000067757:Glucagon-Like Peptide-1 Receptor; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010455:Peptides; D018027:Receptors, Glucagon; C000593835:Glp1r protein, rat; C074636:amyloid beta-protein (25-35); C479460:lixisenatide; D000067758:Glucagon-Like Peptide-2 Receptor; C000605508:Gsk3b protein, rat
keywords: Alzheimer’s disease; Morris water maze; amyloid β-protein; glycogen synthase kinase 3β; lixisenatide; long-term potentiation