Activation of AMP-Activated Protein Kinase Alleviates Homocysteine-Mediated Neurotoxicity in SH-SY5Y Cells
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ORIGINAL PAPER
Activation of AMP-Activated Protein Kinase Alleviates Homocysteine-Mediated Neurotoxicity in SH-SY5Y Cells Youn-Jin Park • Je Won Ko • Yumi Jang Young Hye Kwon
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Received: 8 November 2012 / Revised: 11 April 2013 / Accepted: 19 April 2013 / Published online: 27 April 2013 Ó Springer Science+Business Media New York 2013
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 N1-(b-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 Electronic supplementary material The online version of this article (doi:10.1007/s11064-013-1057-5) contains supplementary material, which is available to authorized users. Y.-J. Park J. W. Ko Y. Jang Y. H. Kwon (&) Department of Food and Nutrition, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea e-mail: [email protected] Y. H. Kwon Research Institute of Human Ecology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea
glycogen synthase kinase-3b 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. Keywords AMPK ER stress Homocysteine Isoflavone Neurotoxicity SH-SY5Y cells
Introduction Increasing numbers of clinical studies have raised the possibility that elevated plasma levels of homocysteine is a risk factor for onset of Alzheimer’s disease as well as atherosclerotic vascular disease [1, 2]. Homocysteine, a sulfur-containing amino acid formed in the course of the metabolism of methionine, is reported to be one of several endoplasmic reticulum (ER) stress inducers in various cell types includin
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