Synergistic induction of ER stress by homocysteine and beta-amyloid in SH-SY5Y cells.
Clinical studies have raised the possibility that elevated plasma levels of homocysteine increase the risk of atherosclerosis, stroke and possibly neurodegenerative diseases such as Alzheimer's disease (AD); however, the direct impact of homocysteine on neuron cells and the mechanism by which it could induce neurodegeneration have yet to be clearly demonstrated. Here, we investigated the effect of homocysteine on endoplasmic reticulum (ER) stress, the suggested mechanism of neurotoxicity, in human neuroblastoma SH-SY5Y cells. The effect of homocysteine on amyloid-beta (Abeta)-induced neurotoxicity and the protective activity of folate were also investigated. Homocysteine led to increased expressions of the binding protein (BiP) and the spliced form of X-box-protein (XBP)-1 mRNAs, suggesting activation of the unfolded-protein response and an increase in apoptosis. When cells were cotreated with homocysteine and Abeta, caspase-3 activity was significantly increased, and expressions of BiP and the spliced form of XBP-1 mRNAs were significantly induced. The neurotoxicity of homocysteine was attenuated by the treatment of cells with folate, as determined by caspase-3 activity and apoptotic body staining. These findings indicate that homocysteine induces ER stress and, ultimately, apoptosis and sensitizes neurons to amyloid toxicity via the synergistic induction of ER stress. Furthermore, a neuroprotective effect of folate against homocysteine-induced toxicity was also observed. Therefore, the findings of our study suggest that ER stress-induced homocysteine toxicity may play an important physiological role in enhancing the pathogenesis of Abeta-induced neuronal degeneration.
Kim
Hyun-Jung
HJ
Department of Food and Nutrition, Seoul National University, Seoul 151-742, South Korea.
Cho
Hyang-Ki
HK
Kwon
Young Hye
YH
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D017209:Apoptosis; D001932:Brain Neoplasms / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005492:Folic Acid / Q000737:chemistry; D006710:Homocysteine / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D011485:Protein Binding; D017382:Reactive Oxygen Species; D014466:Ultraviolet Rays
D016229:Amyloid beta-Peptides; D017382:Reactive Oxygen Species; D006710:Homocysteine; D005492:Folic Acid; D053148:Caspase 3