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An aberrant sugar modification of BACE1 blocks its lysosomal targeting in Alzheimer's disease

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·2015·EMBO Molecular Medicine
DOI 10.15252/emmm.201404438PMC PMC4328647
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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.

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  • Glycosylation has been implicated in the pathological increases in BACE1 stability seen in response to oxidative stress, with bisecting N-acetylglucosamine (GlcNAc) having been shown to prevent lysosomal degradation of BACE1.

    “Glycosylation has also been implicated in the pathological increases in BACE1 stability seen in response to oxidative stress, with bisecting N‐acetylglucosamine (GlcNAc), catalyzed by GlcNAc transferase Gnt‐III having been shown to prevent lysosomal degradation of BACE1.”

    From BACE1: More than just a β‐secretase (2022) · cites this paper as [76]

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Metadata

Authors
Kizuka, Y., Kitazume, S., Fujinawa, R., Saito, T., Iwata, N., Saido, T. C., Nakano, M., Yamaguchi, Y., Hashimoto, Y., Staufenbiel, M., Hatsuta, H., Murayama, S., Manya, H., Endo, T., & Taniguchi, N.
Venue
EMBO Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2015-01-15
Volume
7
Issue
2
Pages
175-189
ISSN
  • 1757-4676
  • 1757-4684
DOI
10.15252/emmm.201404438
PMC
PMC4328647
Cited by
185
References
10
Language
en
Licence
Funders
  • RIKEN
  • Systems Glycobiology Research project
  • Special Postdoctoral Researchers Program
  • Incentive Research
  • Japan Society for the Promotion of Science
  • Scientific Research
  • Scientific Research on Innovative Areas

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