title: Quercetin reduces eIF2α phosphorylation by GADD34 induction.
abstract: The production of amyloid β (Aβ) in the brain from Aβ precursor protein (APP) through γ-secretase is important for the pathogenesis of Alzheimer's disease (AD). Our previous studies have demonstrated that autophagy impairment and endoplasmic reticulum stress increase presenilin 1 expression and enhance γ-secretase activity through the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) and the translation of activating transcription factor 4 (ATF4). However, the inhibitory molecules for γ-secretase are largely unknown. Here, we demonstrate that the levels of ATF4 expression are increased in the brain of APP23 AD model mice; furthermore, these levels enhanced in the brain of APP23 mice crossed with obese and diabetic db/db (Lepr(db/db)) mice. A polyhydroxylated flavonoid, quercetin, suppressed presenilin 1 expression and Aβ secretion in autophagy-impaired cells by the induction of growth arrest and DNA damaged-inducible gene (GADD) 34, which mediates eIF2α dephosphorylation, leading to decreased ATF4 expression. GADD34 induction was observed in the brain of wild-type mice, and APP23 mice fed quercetin in their diet. After the long-term feeding of quercetin, deterioration in memory assessed by freezing behavior was delayed in APP23 mice. These results indicate that quercetin may reduce eIF2α phosphorylation and ATF4 expression through GADD34 induction in the brain, leading to the improvement of memory in aged mice and the delay of deterioration in memory at the early stage of AD in AD model mice.
authors.affiliation: Department of Neurobiology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Hayakawa
authors.affiliation: Department of Neurobiology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Itoh
authors.affiliation: Department of Neurobiology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ohta
authors.affiliation: Department of Neurobiology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Shimo
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Neurobiology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Ueda
authors.affiliation: Department of Neurobiology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Miao-xing
authors.initials: MX
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Emika
authors.initials: E
authors.lastname: Nishida
authors.affiliation: Department of Neurobiology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Saiful
authors.initials: S
authors.lastname: Islam
authors.affiliation: Department of Neurobiology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Suzuki
authors.affiliation: Department of Neurobiology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Ohzawa
authors.affiliation: National Food Research Institute, National Agriculture and Food Research Organization, Tsukuba, Ibaraki, Japan.
authors.forename: Masuko
authors.initials: M
authors.lastname: Kobori
authors.affiliation: Department of Neurology and Geriatrics, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Inuzuka
authors.affiliation: Department of Neurobiology, Gifu University Graduate School of Medicine, Gifu, Japan. Electronic address: tnakagaw@gifu-u.ac.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Nakagawa
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D000071187:Autophagy-Related Protein 5; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003214:Conditioning, Classical / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D053764:Presenilin-1 / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology* / Q000627:therapeutic use; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C497109:ATF4 protein, human; C502778:ATG5 protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000975:Antioxidants; D000071187:Autophagy-Related Protein 5; D004268:DNA-Binding Proteins; C103652:Elf2 protein, mouse; D008869:Microtubule-Associated Proteins; D010446:Peptide Fragments; D053764:Presenilin-1; D054411:Receptors, Leptin; D014157:Transcription Factors; C075222:amyloid beta-protein (1-42); C515447:leptin receptor, mouse; D051701:Activating Transcription Factor 4; D011794:Quercetin; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1
keywords: ATF4; Alzheimer's disease; Amyloid-β; GADD34; Quercetin