title: Gastrodin suppresses BACE1 expression under oxidative stress condition via inhibition of the PKR/eIF2α pathway in Alzheimer's disease.
abstract: The expression of β-site APP-cleaving enzyme 1 (BACE1) is increased in the brain of late-onset sporadic Alzheimer's disease (AD) and oxidative stress may be the potential cause of this event. The phenolic glucoside gastrodin (Gas), a main component of a Chinese herbal medicine Gastrodia elata Blume, has been demonstrated to display antioxidant activity and suppresses BACE1 expression. However, the mechanisms by which Gas suppresses BACE1 expression are not clear. Morris water maze test was performed to assess the effect of Gas treatment on memory impairments in Tg2576 mice. The level of oxidative stress in the brain of Tg2576 mice was determined by measuring the superoxide dismutase (SOD) activity, catalase (CAT) activity, and the levels of malondialdehyde (MDA) and ROS. In vivo and in vitro, we detected the expression levels of BACE1, pPKRThr446, PKR, pPERKThr981, PERK, peIF2αSer51, and eIF2α using western blot analysis. We found that Gas improved learning and memory abilities of Tg2576 transgenic mice and attenuated intracellular oxidative stress in hippocampi of Tg2576 mice. We discovered that the expression levels of BACE1, activated PKR (pPKRThr446) and activated eIF2α (peIF2αSer51) were elevated in the brains of Tg2576 mice and hydrogen peroxide (H2O2)-stimulated SH-SY5Y cells. Moreover, peptide PKR inhibitor (PRI) and Gas down-regulated BACE1 expression in Tg2576 mice and H2O2-stimulated SH-SY5Y cells by inhibiting activation of PKR and eIF2α. Gas alleviates memory deficits in mice and suppresses BACE1 expression by inhibiting the protein kinase/Eukaryotic initiation factor-2α (PKR/eIF2α) pathway. The research suggested that Gas may develop as an drug candidate in neurodegenerative diseases.
authors.affiliation: Department of Neurology, Huaihe Hospital of Henan University, Kaifeng 475000, China.
authors.forename: J-S
authors.initials: JS
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Huaihe Hospital of Henan University, Kaifeng 475000, China.
authors.forename: S-F
authors.initials: SF
authors.lastname: Zhou
authors.affiliation: Department of Neurology, Huaihe Hospital of Henan University, Kaifeng 475000, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Neurology, Huaihe Hospital of Henan University, Kaifeng 475000, China.
authors.forename: J-N
authors.initials: JN
authors.lastname: Guo
authors.affiliation: Department of Neurology, Huaihe Hospital of Henan University, Kaifeng 475000, China.
authors.forename: H-M
authors.initials: HM
authors.lastname: Liang
authors.affiliation: Department of Neurology, Huaihe Hospital of Henan University, Kaifeng 475000, China; Department of Neurobiology, College of Life Sciences, Henan University, Kaifeng 475004, China. Electronic address: dengjinbohn@163.com.
authors.forename: J-B
authors.initials: JB
authors.lastname: Deng
authors.affiliation: Department of Neurology, Huaihe Hospital of Henan University, Kaifeng 475000, China. Electronic address: hewy001@126.com.
authors.forename: W-Y
authors.initials: WY
authors.lastname: He
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001592:Benzyl Alcohols / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005960:Glucosides / Q000008:administration & dosage*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress; D015398:Signal Transduction / Q000187:drug effects; D065852:Spatial Memory / Q000187:drug effects; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D001592:Benzyl Alcohols; D005960:Glucosides; C045345:gastrodin; D019892:eIF-2 Kinase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: Alzheimer’s disease; BACE1; PKR; eIF2α; gastrodin; oxidative stress