title: Lixisenatide attenuates the detrimental effects of amyloid β protein on spatial working memory and hippocampal neurons in rats.
abstract: Type 2 diabetes mellitus(T2DM) is a risk factor of Alzheimer's disease (AD), which is most likely linked to impairments of insulin signaling in the brain. Hence, drugs enhancing insulin signaling may have therapeutic potential for AD. Lixisenatide, a novel long-lasting glucagon-like peptide 1 (GLP-1) analogue, facilitates insulin signaling and has neuroprotective properties. We previously reported the protective effects of lixisenatide on memory formation and synaptic plasticity. Here, we describe additional key neuroprotective properties of lixisenatide and its possible molecular and cellular mechanisms against AD-related impairments in rats. The results show that lixisenatide effectively alleviated amyloid β protein (Aβ) 25-35-induced working memory impairment, reversed Aβ25-35-triggered cytotoxicity on hippocampal cell cultures, and prevented against Aβ25-35-induced suppression of the Akt-MEK1/2 signaling pathway. Lixisenatide also reduced the Aβ25-35 acute application induced intracellular calcium overload, which was abolished by U0126, a specific MEK1/2 inhibitor. These results further confirmed the neuroprotective and cytoprotective action of lixisenatide against Aβ-induced impairments, suggesting that the protective effects of lixisenatide may involve the activation of the Akt-MEK1/2 signaling pathway and the regulation of intracellular calcium homeostasis.
authors: Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan 030001, China.
authors: Hong-Yan
authors: HY
authors: Cai
authors: Department of Physiology, Shanxi Medical University, Taiyuan 030001, China.
authors: Zhao-Jun
authors: ZJ
authors: Wang
authors: Division of Biomed and Life Sciences, Faculty of Health and Medicine Lancaster University, Lancaster, LA1 4YQ, UK.
authors: Christian
authors: C
authors: Hölscher
authors: Department of Physiology, Shanxi Medical University, Taiyuan 030001, China.
authors: Li
authors: L
authors: Yuan
authors: Department of Physiology, Shanxi Medical University, Taiyuan 030001, China.
authors: Jun
authors: J
authors: Zhang
authors: Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan 030001, China.
authors: Peng
authors: P
authors: Sun
authors: Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan 030001, China.
authors: Jing
authors: J
authors: Li
authors: Department of Physiology, Shanxi Medical University, Taiyuan 030001, China.
authors: Wei
authors: W
authors: Yang
authors: Department of Physiology, Shanxi Medical University, Taiyuan 030001, China.
authors: Mei-Na
authors: MN
authors: Wu
authors: Department of Physiology, Shanxi Medical University, Taiyuan 030001, China. Electronic address: jinshunqi2009@163.com.
authors: Jin-Shun
authors: JS
authors: Qi
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects*; D018782:Maze Learning / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D061251:Primary Cell Culture; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D000067758:Glucagon-Like Peptide-2 Receptor
chemical_list: D016229:Amyloid beta-Peptides; D002070:Butadienes; D002118:Calcium; D018696:Neuroprotective Agents; D009570:Nitriles; D010446:Peptide Fragments; D010455:Peptides; C113580:U 0126; C074636:amyloid beta-protein (25-35); C479460:lixisenatide; D000067758:Glucagon-Like Peptide-2 Receptor
keywords: Akt-MEK1/2 signal pathway; Amyloid β protein; Cell viability; Intracellular calcium concentration; Lixisenatide; Working memory