| Item type |
デフォルトアイテムタイプ_（フル）(1) |
| 公開日 |
2023-03-18 |
| タイトル |
|
|
タイトル |
An aberrant sugar modification of BACE1 blocks its lysosomal targeting in Alzheimer's disease |
|
言語 |
en |
| 作成者 |
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
|
| アクセス権 |
|
|
アクセス権 |
open access |
|
アクセス権URI |
http://purl.org/coar/access_right/c_abf2 |
| 権利情報 |
|
|
権利情報 |
© 2015 The Authors. 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. |
| 主題 |
|
|
主題Scheme |
Other |
|
主題 |
Alzheimer’s disease |
| 主題 |
|
|
主題Scheme |
Other |
|
主題 |
amyloid-b |
| 主題 |
|
|
主題Scheme |
Other |
|
主題 |
BACE1 |
| 主題 |
|
|
主題Scheme |
Other |
|
主題 |
bisecting GlcNAc |
| 主題 |
|
|
主題Scheme |
Other |
|
主題 |
GnT-III |
| 内容記述 |
|
|
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. |
|
言語 |
en |
| 内容記述 |
|
|
内容記述タイプ |
Other |
|
内容記述 |
This work was supported by RIKEN (the Systems Glycobiology Research project to NT, Special Postdoctoral Researchers Program to YK, and Incentive Research Grant to YK) and by the Japan Society for the Promotion of Science (JSPS) (Grant-in-Aid for Scientific Research (A) to NT and for Scientific Research on Innovative Areas to HM). |
| 言語 |
|
|
言語 |
eng |
| 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 |
| 出版タイプ |
|
|
出版タイプ |
VoR |
|
出版タイプResource |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| 関連情報 |
|
|
|
識別子タイプ |
DOI |
|
|
関連識別子 |
10.15252/emmm.201404438 |
| 関連情報 |
|
|
|
識別子タイプ |
PMID |
|
|
関連識別子 |
25592972 |
| 関連情報 |
|
|
|
識別子タイプ |
DOI |
|
|
関連識別子 |
https://doi.org/10.15252/emmm.201404438 |
| 収録物識別子 |
|
|
収録物識別子タイプ |
ISSN |
|
収録物識別子 |
1757-4676 |
| 収録物識別子 |
|
|
収録物識別子タイプ |
ISSN |
|
収録物識別子 |
1757-4684 |
| 開始ページ |
|
|
開始ページ |
175 |
| 書誌情報 |
EMBO Molecular Medicine
EMBO Molecular Medicine
巻 7,
号 2,
p. 175-189,
発行日 2015-02-01
|
| 旧ID |
48670 |
EMBOMolMed_7_175.pdf (2.3 MB)
