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An aberrant sugar modification of BACE1 blocks its lysosomal targeting in Alzheimer's disease
http://hdl.handle.net/10069/35112
http://hdl.handle.net/10069/3511290c19c1f-43a2-4104-9d6f-f401a1f65f26
名前 / ファイル | ライセンス | アクション |
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EMBO7_175.pdf (2.4 MB)
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Item type | 学術雑誌論文 / Journal Article(1) | |||||
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公開日 | 2015-03-03 | |||||
タイトル | ||||||
タイトル | An aberrant sugar modification of BACE1 blocks its lysosomal targeting in Alzheimer's disease | |||||
言語 | ||||||
言語 | eng | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | Alzheimer's disease (AD) | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | Amyloid-β (Aβ) | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | BACE1 | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | Bisecting GlcNAc | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | GnT-III (Mgat3) | |||||
資源タイプ | ||||||
資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
資源タイプ | journal article | |||||
著者 |
Kizuka, Yasuhiko
× Kizuka, Yasuhiko× Kitazume, Shinobu× Fujinawa, Reiko× Saito, Takashi× Iwata, Nobuhisa× Saido, Takaomi C.× Nakano, Miyako× Yamaguchi, Yoshiki× Hashimoto, Yasuhiro× Staufenbiel, Matthias× Hatsuta, Hiroyuki× Murayama, Shigeo× Manya, Hiroshi× Endo, Tamao× Taniguchi, Naoyuki |
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抄録 | ||||||
内容記述タイプ | Abstract | |||||
内容記述 | 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. | |||||
書誌情報 |
EMBO Molecular Medicine 巻 7, 号 2, p. 175-189, 発行日 2015-02-01 |
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出版者 | ||||||
出版者 | EMBO Press | |||||
ISSN | ||||||
収録物識別子タイプ | ISSN | |||||
収録物識別子 | 17574676 | |||||
EISSN | ||||||
収録物識別子タイプ | ISSN | |||||
収録物識別子 | 17574684 | |||||
DOI | ||||||
関連タイプ | isIdenticalTo | |||||
識別子タイプ | DOI | |||||
関連識別子 | 10.15252/emmm.201404438 | |||||
権利 | ||||||
権利情報 | c 2014 EMBO | |||||
権利 | ||||||
権利情報 | This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. | |||||
著者版フラグ | ||||||
出版タイプ | VoR | |||||
出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||
引用 | ||||||
内容記述タイプ | Other | |||||
内容記述 | EMBO Molecular Medicine, 7(2), pp.175-189; 2015 |