title: Ciliary neurotrophic factor protects SH-SY5Y neuroblastoma cells against Aβ1-42-induced neurotoxicity via activating the JAK2/STAT3 axis.
abstract: The neurotoxicity of aggregated amyloid beta (Aβ) has been implicated as a critical cause in the pathogenesis of Alzheimer's disease (AD), which leads to neuronal cell damage by inducing oxidative stress and consequently triggering cell apoptosis. Recently, Aβ-dependent inactivation of the Janus tyrosine kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway was found to play a critical role in the memory impairment related to AD. Previous research indicated that JAK2/STAT3 axis inactivation might be the result of aberrant reactive oxygen species (ROS) generation induced by Aβ in neurons. As the JAK2/STAT3 axis is a major transducer of ciliary neurotrophic factor (CNTF)-mediated neuroprotective activity, this study extensively evaluated whether activation of the JAK2/STAT3 axis by CNTF was responsible for the neuroprotective effect of this protein against Aβ1-42-induced cytotoxicity, oxidative injury and cell apoptosis in human SH-SY5Y neuroblastoma cells. Our data showed that CNTF could attenuate or restore cell injury induced by Aβ1-42 in human SH-SY5Y neuroblastoma cells through activating the JAK2/STAT3 signaling pathway. Furthermore, CNTF strikingly prevented Aβ1-42-induced mitochondrial dysfunction and activation of mitogen-activated protein kinases (MAPKs), an effect that could be potently attenuated by the specific JAK2 inhibitor AG490. In summary, this study confirmed the detailed mechanism accounting for CNTF's protective effect against Aβ1-42-induced cytotoxic events in human SH-SY5Y neuroblastoma cells - information which might significantly contribute to better understanding of the mechanism of action of CNTF as well as providing a novel target in AD therapy.
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.affiliation: Minhao Xie, Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, Jiangsu Province, China, phone: +86-510-85514482; fax: +86-510-85514482, e-mail: nypd0723@gmail.com.
authors.forename: Minhao
authors.initials: M
authors.lastname: Xie
authors.forename: Ling
authors.initials: L
authors.lastname: Zhu
authors.forename: Xue
authors.initials: X
authors.lastname: Zhu
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.forename: Fanfan
authors.initials: F
authors.lastname: Zhou
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism*; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D020934:Ciliary Neurotrophic Factor; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C075222:amyloid beta-protein (1-42); C507924:JAK2 protein, human; D053614:Janus Kinase 2