title: Excess APP O-glycosylation by GalNAc-T6 decreases Aβ production.
abstract: Alterations of the structure and/or amount of glycans present on proteins are associated with many diseases. We previously demonstrated that changes in N-glycans alter Aβ production. In the present study, we focused on the relationship between Alzheimer's disease (AD) and O-glycan, another type of glycan. The UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferase (GalNAc-T) family functions in the first step of mucin-type O-glycan synthesis. Analysis of the expression of GalNAc-Ts in the human brain using real-time PCR revealed that the expression of several GalNAc-Ts was altered with sporadic AD progression. Three of these GalNAc-Ts (GalNAc-T1, GalNAc-T4 and GalNAc-T6) were transfected into HEK293T cells to examine their impact on Aβ production. Transfection of GalNAc-T6 significantly reduced both Aβ1-40 and Aβ1-42 generation, but GalNAc-T1 and GalNAc-T4 only reduced Aβ1-40 generation. Although these three GalNAc-Ts exhibited enzymatic activities on soluble amyloid precursor protein (APP), the GalNAc transferase activity of GalNAc-T6 to APP was most prominent. The expression of α-secretase and β-secretase was slightly altered in the transfected cells, but the activities of α-secretase and β-secretase were not significantly altered. These data suggest that excess O-glycosylation on APP by GalNAc-T6 inhibits Aβ production.
authors.affiliation: Molecular Glycobiology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakaecho, Itabashi-ku, Tokyo 173-0015, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Akasaka-Manya
authors.affiliation: Molecular Glycobiology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakaecho, Itabashi-ku, Tokyo 173-0015, Japan.|Department of Biological Sciences, Molecular Neuroscience Laboratory, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji-shi, Tokyo 192-0397, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Kawamura
authors.affiliation: Proteome Research, Research Team for Mechanism of Aging.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tsumoto
authors.affiliation: Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakaecho, Itabashi-ku, Tokyo 173-0015, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Disease Glycomics Team, RIKEN-Max Planck Joint Research Center, Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Tachida
authors.affiliation: Disease Glycomics Team, RIKEN-Max Planck Joint Research Center, Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Kitazume
authors.affiliation: Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakaecho, Itabashi-ku, Tokyo 173-0015, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hatsuta
authors.affiliation: Proteome Research, Research Team for Mechanism of Aging.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Miura
authors.affiliation: Department of Biological Sciences, Molecular Neuroscience Laboratory, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji-shi, Tokyo 192-0397, Japan.
authors.forename: Shin-Ichi
authors.initials: SI
authors.lastname: Hisanaga
authors.affiliation: Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakaecho, Itabashi-ku, Tokyo 173-0015, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.affiliation: Department of Biochemistry, School of Medicine, Fukushima Medical University, 1 Hikariga-oka, Fukushima City 960-1295, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: Molecular Glycobiology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakaecho, Itabashi-ku, Tokyo 173-0015, Japan manya@tmig.or.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Manya
authors.affiliation: Molecular Glycobiology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakaecho, Itabashi-ku, Tokyo 173-0015, Japan endo@tmig.or.jp.
authors.forename: Tamao
authors.initials: T
authors.lastname: Endo
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D006031:Glycosylation; D057809:HEK293 Cells; D006801:Humans; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D017350:N-Acetylgalactosaminyltransferases; C121529:UDP-N-acetylgalactosamine polypeptide N-acetylgalactosaminyltransferase 6; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer’s disease; GalNAc-T; O-glycan; amyloid precursor protein