title: An aberrant sugar modification of BACE1 blocks its lysosomal targeting in Alzheimer's disease.
abstract: The β-site amyloid precursor protein cleaving enzyme-1 (BACE1), an essential protease for the generation of amyloid-β (Aβ) peptide, is a major drug target for Alzheimer's disease (AD). However, there is a concern that inhibiting BACE1 could also affect several physiological functions. Here, we show that BACE1 is modified with bisecting N-acetylglucosamine (GlcNAc), a sugar modification highly expressed in brain, and demonstrate that AD patients have higher levels of bisecting GlcNAc on BACE1. Analysis of knockout mice lacking the biosynthetic enzyme for bisecting GlcNAc, GnT-III (Mgat3), revealed that cleavage of Aβ-precursor protein (APP) by BACE1 is reduced in these mice, resulting in a decrease in Aβ plaques and improved cognitive function. The lack of this modification directs BACE1 to late endosomes/lysosomes where it is less colocalized with APP, leading to accelerated lysosomal degradation. Notably, other BACE1 substrates, CHL1 and contactin-2, are normally cleaved in GnT-III-deficient mice, suggesting that the effect of bisecting GlcNAc on BACE1 is selective to APP. Considering that GnT-III-deficient mice remain healthy, GnT-III may be a novel and promising drug target for AD therapeutics.
authors.affiliation: Disease Glycomics Team, RIKEN-Max Planck Joint Research Center Global Research Cluster RIKEN, Wako, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kizuka
authors.affiliation: Disease Glycomics Team, RIKEN-Max Planck Joint Research Center Global Research Cluster RIKEN, Wako, Japan shinobuk@riken.jp dglycotani@riken.jp.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Kitazume
authors.affiliation: Disease Glycomics Team, RIKEN-Max Planck Joint Research Center Global Research Cluster RIKEN, Wako, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Fujinawa
authors.affiliation: Laboratory for Proteolytic Neuroscience RIKEN Brain Science Institute, Wako, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.affiliation: Laboratory for Proteolytic Neuroscience RIKEN Brain Science Institute, Wako, Japan Department of Genome-based Drug Discovery, Unit of Molecular Medicinal Sciences, Graduate School of Biomedical Sciences Nagasaki University, Nagasaki, Japan.
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Iwata
authors.affiliation: Laboratory for Proteolytic Neuroscience RIKEN Brain Science Institute, Wako, Japan.
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
authors.affiliation: Graduate School of Advanced Sciences of Matter Hiroshima University, Higashihiroshima Hiroshima, Japan.
authors.forename: Miyako
authors.initials: M
authors.lastname: Nakano
authors.affiliation: Structural Glycobiology Team, RIKEN-Max Planck Joint Research Center Global Research Cluster RIKEN, Wako, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Department of Biochemistry, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.affiliation: Department of Neuropathology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hatsuta
authors.affiliation: Department of Neuropathology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku Tokyo, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.affiliation: Molecular Glycobiology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Manya
authors.affiliation: Molecular Glycobiology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku Tokyo, Japan.
authors.forename: Tamao
authors.initials: T
authors.lastname: Endo
authors.affiliation: Disease Glycomics Team, RIKEN-Max Planck Joint Research Center Global Research Cluster RIKEN, Wako, Japan shinobuk@riken.jp dglycotani@riken.jp.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Taniguchi
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006031:Glycosylation; D006801:Humans; D008247:Lysosomes / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017351:N-Acetylglucosaminyltransferases / Q000172:deficiency / Q000235:genetics; D021381:Protein Transport
chemical_list: D016229:Amyloid beta-Peptides; D017351:N-Acetylglucosaminyltransferases; C054599:beta-1,4-mannosyl-glycoprotein beta-1,4-N-acetylglucosaminyltransferase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D000117:Acetylglucosamine
keywords: Alzheimer's disease (AD); BACE1; GnT‐III (Mgat3); amyloid‐β (Aβ); bisecting GlcNAc