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.
Highlights
Alzheimer’s disease (AD) is a devastating dementia, with the number of patients estimated to be ~0.5% of the global population (Abbott, 2011; Selkoe, 2012)
We first show that b-site amyloid precursor protein cleaving enzyme-1 (BACE1) is highly modified with bisecting GlcNAc in the brains of AD patients
Our analyses of GnT-IIIdeficient mice show that lack of bisecting GlcNAc causes a shift in the intracellular localization of BACE1 from early endosomes, where the substrate amyloid precursor protein (APP) is mainly localized, to late endosomes/lysosomes, thereby enhancing its lysosomal degradation
Summary
Alzheimer’s disease (AD) is a devastating dementia, with the number of patients estimated to be ~0.5% of the global population (Abbott, 2011; Selkoe, 2012). Deposition of amyloid-b (Ab) peptide in the brain is considered to represent the initial event in disease development (Karran et al, 2011). Ab is generated by the two-step proteolytic cleavage of amyloid precursor protein (APP), which is catalyzed by the b-site APP cleaving enzyme-1 (BACE1, designated as b-secretase) (Vassar et al, 2014) and c-secretase (De Strooper & Annaert, 2010). Current trials to develop c-secretase inhibitors have been unsuccessful due to serious side effects, probably as a result of disturbing the signaling of Notch (De Strooper et al, 1998), another substrate for c-secretase. BACE1 protease has substrates other than APP (Kuhn et al, 2012; Vassar et al, 2014), including a2,6sialyltransferase (Kitazume et al, 2001), P-selectin glycoprotein ligand-1 (PSGL-1) (Lichtenthaler et al, 2003), APP homolog proteins (APLP1 and APLP2) (Eggert et al, 2004; Li & Sudhof, 2004; Pastorino et al, 2004), low-density lipoprotein receptor-related protein (LRP)
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