GASTRODIN SUPPRESSES BACE1 EXPRESSION UNDER OXIDATIVE STRESS CONDITION VIA INHIBITION OF THE PKR/eIF2α PATHWAY IN ALZHEIMER'S DISEASE

The expression of beta-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, pPKR(Thr446), PKR, pPERK(Thr981), PERK, peIF2 alpha(Ser51), and eIF2 alpha 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 (pPKR(Thr446)) and activated eIF2 alpha (peIF2 alpha(Ser51)) 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 eIF2 alpha. Gas alleviates memory deficits in mice and suppresses BACE1 expression by inhibiting the protein kinase/ Eukaryotic initiation factor-2 alpha (PKR/eIF2 alpha) pathway. The research suggested that Gas may develop as an drug candidate in neurodegenerative diseases. (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved.