title: Increased GADD34 in oligodendrocytes in Alzheimer's disease.
abstract: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) and abnormally phosphorylated tau which contribute to endoplasmic reticulum (ER) stress. Previous studies demonstrated that Aβ and a truncated fragment of Aβ induced death of oligodendrocytes in vitro. In addition, a triple-transgenic AD mouse model exhibits significant region-specific alterations in myelination patterns at time points preceding the appearance of Aβ accumulation. The growth arrest and DNA damage protein (GADD) 34 is up-regulated in response to ER stress and regulates subunit of protein phosphatase 1 (PP1) complex that dephosphorylates eukaryotic translation initiator factor 2α (elF2α). Thus, GADD34 is known as an ER stress regulator or ER stress marker. In a recent study, GADD34 was induced in the spinal cord glial cells of an amyotrophic lateral sclerosis (ALS) mouse model. It is interesting that reduced GADD34 delayed the onset of ALS and prolonged the survival period in the mouse model. In this study, we have demonstrated that GADD34 was increased in neurons of human AD brains. Additionally, this finding was also observed in oligodendrocytes in human AD brains. Furthermore, we showed that the expression levels of GADD34 in neurons and oligodendrocytes were significantly increased in the early stage of AD in the mouse model. As oligodendrocytes were more affected in the early stages of AD in this experimental model, ER stress of Aβ oligomers may be more related to oligodendrocytes than to neurons. These results suggest that GADD34 could be a therapeutic target for preventing ER stress in neuronal cells in AD.
authors.affiliation: Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Japan; Department of Neurology, Graduate School of Medicine, Kyoto University, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Honjo
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ayaki
authors.affiliation: Department of Neurology and Neuroscience, Osaka City University Medical School, Japan.
authors.forename: Takami
authors.initials: T
authors.lastname: Tomiyama
authors.affiliation: Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Horibe
authors.affiliation: Department of Neurology, Graduate School of Medicine, Wakayama Medical University, Japan.
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Clinical Neuroscience, Osaka City University Medical School, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mori
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Japan. Electronic address: kawakami.koji.4e@kyoto-u.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Kawakami
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism*; D054645:Protein Phosphatase 1 / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1
keywords: Alzheimer’s disease; ER stress; GADD34; Oligodendrocytes