title: Sphingosine kinase-1 protects differentiated N2a cells against beta-amyloid25-35-induced neurotoxicity via the mitochondrial pathway.
abstract: Although the etiology of Alzheimer's disease (AD) is not fully understood, multiple lines of evidence suggests the importance of amyloid-β (Aβ) in the initiation/progression of the disease. Aβ has been shown to induce neuronal apoptosis via the sphingomyelin/ceramide pathway. This study was designed to elucidate whether the sphingosine kinase-1 (SPK1), a critical regulator of the ceramide/sphingosine 1-phosphate rheostat, plays a pivotal role in the regulation of death and survival of differentiated neuro-2a cells in response to beta-amyloid peptide fragment 25-35 (Aβ25-35). These results show that the expression of SPK1 was markedly decreased in Aβ25-35-induced neurotoxicity, as evidenced by the decreased cell viability and the increased apoptotic rate. Overexpression of SPK1 significantly attenuated Aβ25-35-induced neurotoxicity, whereas silencing the expression of SPK1 exacerbated it. Moreover, overexpression of SPK1 can significantly attenuate Aβ25-35-induced upregulation of Bax and rehabilitate the level of Bcl-2; concomitantly, it can ameliorate mitochondrial ultrastructure. These studies demonstrate that overexpression of SPK1 may moderate Aβ25-35-induced neurotoxicity by regulating the Bcl-2/Bax ratio and improving mitochondrial ultrastructure. Based on these findings, SPK1 is a potential therapeutic target for AD.
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Dadao, Wuhan, 430022, Hubei Province, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Bingjie
authors.initials: B
authors.lastname: Lv
authors.forename: Rong
authors.initials: R
authors.lastname: Ma
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.forename: Yaoyan
authors.initials: Y
authors.lastname: Dun
authors.forename: Shenggang
authors.initials: S
authors.lastname: Sun
authors.forename: Gang
authors.initials: G
authors.lastname: Li
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D020258:Neurotoxicity Syndromes / Q000517:prevention & control*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000633:toxicity*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis / Q000627:therapeutic use*; D051381:Rats; D000099157:Sphingosine Kinase
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase; C074636:amyloid beta-protein (25-35)