Isoflavones prevent endoplasmic reticulum stress-mediated neuronal degeneration by inhibiting tau hyperphosphorylation in SH-SY5Y cells.
Several studies have demonstrated a protective effect of estrogen against the risk of developing neurodegenerative diseases; however, the molecular mechanisms involved have not been fully addressed. Isoflavones have been proposed as potential alternatives to estrogen replacement therapy. Therefore, in the present study, we investigated effects of isoflavones on cell death and tau phosphorylation in SH-SY5Y human neuroblastoma cells. Cells were treated with tunicamycin (TM) to induce endoplasmic reticulum (ER) stress-mediated toxicity, which is involved in development of neurodegenerative diseases. Treatment of cells with either 17beta-estradiol or isoflavones (either genistein or daidzein) significantly protected cells against cell death. The protective effect against cell death was blocked by a specific estrogen receptor blocker, ICI 182,780, suggesting that isoflavones protect against cell death via estrogen receptor-dependent pathways. Isoflavones also suppressed ER stress as determined by decreased expressions of the immunoglobulin binding protein (BiP) mRNA, spliced X-box binding protein-1 (Xbp-1) mRNAs, and C/EBP homologous protein (CHOP). TM activated glycogen synthase kinase 3beta (GSK3beta), a kinase involved in tau phosphorylation; in contrast, isoflavones inactivated GSK3beta and decreased tau hyperphosphorylation. In conclusion, our results clearly demonstrate that isoflavones prevent ER stress-mediated neurotoxicity by inhibiting tau hyperphosphorylation in SH-SY5Y cells.
Park
Youn-Jin
YJ
Department of Food and Nutrition, Seoul National University, Seoul, Republic of Korea.
Jang
Yu-mi
YM
Kwon
Young Hye
YH
D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D019833:Genistein / Q000494:pharmacology / Q000627:therapeutic use; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology* / Q000627:therapeutic use; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D048789:Phytoestrogens / Q000494:pharmacology / Q000627:therapeutic use; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D011960:Receptors, Estrogen / Q000378:metabolism; D013025:Glycine max / Q000737:chemistry*; D051742:Transcription Factor CHOP / Q000378:metabolism; D014415:Tunicamycin; D016875:tau Proteins / Q000378:metabolism*
D007529:Isoflavones; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D048789:Phytoestrogens; D010936:Plant Extracts; D011960:Receptors, Estrogen; D016875:tau Proteins; D014415:Tunicamycin; D051742:Transcription Factor CHOP; D004958:Estradiol; C004742:daidzein; D019833:Genistein; D038362:Glycogen Synthase Kinase 3