An aberrant sugar modification of BACE 1 blocks its lysosomal targeting in A lzheimer's disease

Abstract

The β‐site amyloid precursor protein cleaving enzyme‐1 ( BACE 1), 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 BACE 1 could also affect several physiological functions. Here, we show that BACE 1 is modified with bisecting N‐acetylglucosamine (Glc NA c), a sugar modification highly expressed in brain, and demonstrate that AD patients have higher levels of bisecting Glc NA c on BACE 1. Analysis of knockout mice lacking the biosynthetic enzyme for bisecting Glc NA c, GnT‐ III ( Mgat3 ), revealed that cleavage of Aβ‐precursor protein ( APP ) by BACE 1 is reduced in these mice, resulting in a decrease in Aβ plaques and improved cognitive function. The lack of this modification directs BACE 1 to late endosomes/lysosomes where it is less colocalized with APP , leading to accelerated lysosomal degradation. Notably, other BACE 1 substrates, CHL 1 and contactin‐2, are normally cleaved in GnT‐ III ‐deficient mice, suggesting that the effect of bisecting Glc NA c on BACE 1 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. image Bisecting Glc NA c modification of BACE 1 by GnT‐ III is a novel regulator of BACE 1 stability. Loss of GnT‐ III curbs BACE 1‐mediated Aβ plaque generation. Hence, the bisecting Glc NA c biosynthesis pathway is a promising new target for AD therapy. Alzheimer's disease ( AD ) patients present high levels of bisecting Glc NA c modifications on BACE 1. Loss of bisecting Glc NA c reduces BACE 1‐mediated Aβ generation, leading to amelioration of AD pathology. Loss of bisecting Glc NA c reduces BACE 1– APP localization. The enzyme responsible for the biosynthesis of bisecting Glc NA c, G n T ‐ III , is therefore a potential new drug target for AD .