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However, there is a concern that inhibiting BACE1 could also affect several physiological functions. Here, we show that BACE1 is modified with bisecting N\u2010acetylglucosamine (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\u2010III (\n                    <jats:italic>Mgat3<\/jats:italic>\n                    ), revealed that cleavage of A\u03b2\u2010precursor protein (APP) by BACE1 is reduced in these mice, resulting in a decrease in A\u03b2 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\u20102, are normally cleaved in GnT\u2010III\u2010deficient mice, suggesting that the effect of bisecting GlcNAc on BACE1 is selective to APP. Considering that GnT\u2010III\u2010deficient mice remain healthy, GnT\u2010III may be a novel and promising drug target for AD therapeutics.\n                  <\/jats:p>","DOI":"10.15252\/emmm.201404438","type":"journal-article","created":{"date-parts":[[2015,1,15]],"date-time":"2015-01-15T22:06:13Z","timestamp":1421359573000},"page":"175-189","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":184,"title":["An aberrant sugar modification of BACE1 blocks its lysosomal targeting in Alzheimer's disease"],"prefix":"10.1038","volume":"7","author":[{"given":"Yasuhiko","family":"Kizuka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinobu","family":"Kitazume","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reiko","family":"Fujinawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhisa","family":"Iwata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaomi C","family":"Saido","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miyako","family":"Nakano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiki","family":"Yamaguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Staufenbiel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Hatsuta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeo","family":"Murayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Manya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamao","family":"Endo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoyuki","family":"Taniguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,1,15]]},"reference":[{"key":"BFEMMM201404438_CR1","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1038\/475S2a","volume":"475","author":"A Abbott","year":"2011","unstructured":"Abbott A (2011) Dementia: a problem for our age. 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