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Loss of bisected glycan decreases Abeta generation by relocating BACE1 to the lysosomal degradation pathway

Kizuka, Yasushiko and Kitazume, Shinobu and Fujinawa, Reiko and Saito, Takashi and Iwata, Nobuhisa and Saido, Takaomi C and Nakano, Miyako and Yamaguchi, Yoshiki and Hashimoto, Yasuhiro and Staufenbiel, Matthias and Hatsuda, Hisoshi and Endo, Tamao and Taniguchi, Naoyuki (2015) Loss of bisected glycan decreases Abeta generation by relocating BACE1 to the lysosomal degradation pathway. Biochemical Journal, 473 (1). pp. 21-30. ISSN 0264-60211470-8728

Official URL: http://www.science.com

Abstract

The β-site amyloid precursor protein cleaving enzyme-1 (BACE1) is essential for the generation of amyloid-β (Aβ) peptide, the brain deposition of which is central to the pathogenesis of Alzheimer’s disease (AD). BACE1 inhibitors are currently in various stages of therapeutic development. Here, we focus on bisecting GlcNAc, a glycan highly expressed in brain, and show that deletion of its synthesizing enzyme, GnT-III, diminishes amyloid plaque formation through reduced Aβ generation by BACE1. We demonstrate that BACE1 is modified by bisecting
GlcNAc and show that the lack of this glycan directs BACE1 to late endosomes, leading to accelerated lysosomal degradation. Such BACE1 instability is exaggerated by oxidative stress and increases in aged mice. We also reveal that AD patient-derived BACE1 is highly modified
by bisecting GlcNAc. These results show that bisecting GlcNAc is a key pathological modification in the stress-mediated BACE1-Aβ cycle, providing new possibilities for glycantargeted AD therapeutics.

Item Type: Article
Keywords: Alzheimer's Disease BACE1 Glycan
Date Deposited: 13 Oct 2016 00:45
Last Modified: 13 Oct 2016 00:45
URI: https://oak.novartis.com/id/eprint/10669

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