title: Activation of AMP-activated protein kinase alleviates homocysteine-mediated neurotoxicity in SH-SY5Y cells.
abstract: Mammalian AMP-activated protein kinase (AMPK) acts as a metabolite-sensing protein kinase in multiple tissues. Recent studies have shown that AMPK activation also regulates intracellular signaling pathways involved in cellular survival and apoptosis. Previously, we have reported that AMPK activation alleviates the endoplasmic reticulum (ER) stress-mediated neurotoxicity and tau hyperphosphorylation caused by palmitate. Therefore, we investigated whether AMPK activation alleviates ER stress-mediated neurotoxicity in SH-SY5Y human neuroblastoma cells incubated with homocysteine. Regulation of AMPK activity by isoflavone was also determined to investigate the underlying mechanism of its neuroprotective effect. Treatment of SH-SY5Y human neuroblastoma cells with N (1)-(β-D-ribofuranosyl)-5-aminoimidazole-4-carboxamide (AICAR), a pharmacological activator of AMPK, significantly protected cells against cytotoxicity imposed by tunicamycin and homocysteine. Homocysteine significantly suppressed AMPK activation, which was alleviated by AICAR. We observed a significant inhibition of the unfolded protein response by AICAR in cells incubated with homocysteine, suggesting a protective role of AMPK activation against ER stress-mediated neurotoxicity. AICAR also significantly reduced tau hyperphosphorylation by inactivating glycogen synthase kinase-3β and c-Jun N-terminal kinase in cells incubated with homocysteine. Furthermore, treatment of cells with soy isoflavone, genistein and daidzein significantly activated AMPK, which was repressed by tunicamycin and homocysteine. Therefore, our results suggest that AMPK activation by isoflavone as well as AICAR alleviates homocysteine-mediated neurotoxicity in SH-SY5Y cells.
authors.affiliation: Department of Food and Nutrition, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 151-742, Korea.
authors.forename: Youn-Jin
authors.initials: YJ
authors.lastname: Park
authors.forename: Je Won
authors.initials: JW
authors.lastname: Ko
authors.forename: Yumi
authors.initials: Y
authors.lastname: Jang
authors.forename: Young Hye
authors.initials: YH
authors.lastname: Kwon
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D004789:Enzyme Activation; D006710:Homocysteine / Q000633:toxicity*; D006801:Humans; D016133:Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D006710:Homocysteine; D055372:AMP-Activated Protein Kinases