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

作者：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

来源：EMBO Molecular Medicine, 2015, 7(2): 175-189.

DOI：10.15252/emmm.201404438

• Alzheimer's disease
• amyloid-beta
• BACE1
• bisecting GlcNAc
• GnT-III

The beta-site amyloid precursor protein cleaving enzyme-1 (BACE1), an essential protease for the generation of amyloid-beta (A beta) 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 A beta-precursor protein (APP) by BACE1 is reduced in these mice, resulting in a decrease in A beta 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.

• 出版日期2015-2