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


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          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.

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          Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology.

          Mutations in the amyloid precursor protein (APP) gene cause early-onset familial Alzheimer disease (AD) by affecting the formation of the amyloid beta (A beta) peptide, the major constituent of AD plaques. We expressed human APP751 containing these mutations in the brains of transgenic mice. Two transgenic mouse lines develop pathological features reminiscent of AD. The degree of pathology depends on expression levels and specific mutations. A 2-fold overexpression of human APP with the Swedish double mutation at positions 670/671 combined with the V717I mutation causes A beta deposition in neocortex and hippocampus of 18-month-old transgenic mice. The deposits are mostly of the diffuse type; however, some congophilic plaques can be detected. In mice with 7-fold overexpression of human APP harboring the Swedish mutation alone, typical plaques appear at 6 months, which increase with age and are Congo Red-positive at first detection. These congophilic plaques are accompanied by neuritic changes and dystrophic cholinergic fibers. Furthermore, inflammatory processes indicated by a massive glial reaction are apparent. Most notably, plaques are immunoreactive for hyperphosphorylated tau, reminiscent of early tau pathology. The immunoreactivity is exclusively found in congophilic senile plaques of both lines. In the higher expressing line, elevated tau phosphorylation can be demonstrated biochemically in 6-month-old animals and increases with age. These mice resemble major features of AD pathology and suggest a central role of A beta in the pathogenesis of the disease.
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            Metabolism, cell surface organization, and disease.

            Genetic information flows from DNA to macromolecular structures-the dominant force in the molecular organization of life. However, recent work suggests that metabolite availability to the hexosamine and Golgi N-glycosylation pathways exerts control over the assembly of macromolecular complexes on the cell surface and, in this capacity, acts upstream of signaling and gene expression. The structure and number of N-glycans per protein molecule cooperate to regulate lectin binding and thereby the distribution of glycoproteins at the cell surface. Congenital disorders of glycosylation provide insight as extreme hypomorphisms, whereas milder deficiencies may encompass many common chronic conditions, including autoimmunity, metabolic syndrome, and aging. Copyright 2009 Elsevier Inc. All rights reserved.
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              Potent amyloidogenicity and pathogenicity of Aβ43.

              The amyloid-β peptide Aβ42 is known to be a primary amyloidogenic and pathogenic agent in Alzheimer's disease. However, the role of Aβ43, which is found just as frequently in the brains of affected individuals, remains unresolved. We generated knock-in mice containing a pathogenic presenilin-1 R278I mutation that causes overproduction of Aβ43. Homozygosity was embryonic lethal, indicating that the mutation involves a loss of function. Crossing amyloid precursor protein transgenic mice with heterozygous mutant mice resulted in elevated Aβ43, impairment of short-term memory and acceleration of amyloid-β pathology, which accompanied pronounced accumulation of Aβ43 in plaque cores similar in biochemical composition to those observed in the brains of affected individuals. Consistently, Aβ43 showed a higher propensity to aggregate and was more neurotoxic than Aβ42. Other pathogenic presenilin mutations also caused overproduction of Aβ43 in a manner correlating with Aβ42 and with the age of disease onset. These findings indicate that Aβ43, an overlooked species, is potently amyloidogenic, neurotoxic and abundant in vivo.

                Author and article information

                EMBO Mol Med
                EMBO Mol Med
                EMBO Molecular Medicine
                BlackWell Publishing Ltd (Oxford, UK )
                February 2015
                15 January 2015
                : 7
                : 2
                : 175-189
                [1 ]Disease Glycomics Team, RIKEN-Max Planck Joint Research Center, Global Research Cluster, RIKEN Wako, Japan
                [2 ]Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute Wako, Japan
                [3 ]Department of Genome-based Drug Discovery, Unit of Molecular Medicinal Sciences, Graduate School of Biomedical Sciences, Nagasaki University Nagasaki, Japan
                [4 ]Graduate School of Advanced Sciences of Matter, Hiroshima University Higashihiroshima, Hiroshima, Japan
                [5 ]Structural Glycobiology Team, RIKEN-Max Planck Joint Research Center, Global Research Cluster, RIKEN Wako, Japan
                [6 ]Department of Biochemistry, Fukushima Medical University School of Medicine Fukushima, Japan
                [7 ]Novartis Institutes for Biomedical Research Basel, Switzerland
                [8 ]Department of Neuropathology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology Itabashi-ku, Tokyo, Japan
                [9 ]Molecular Glycobiology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology Itabashi-ku, Tokyo, Japan
                Author notes
                * Corresponding author. Tel: +81 48 467 9616; Fax: +81 48 467 9617; E-mail: shinobuk@ 123456riken.jp
                ** Corresponding author. Tel: +81 48 467 9616; Fax: +81 48 467 9617; E-mail: dglycotani@ 123456riken.jp

                Subject Categories Neuroscience

                © 2015 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                : 04 August 2014
                : 02 December 2014
                : 12 December 2014
                Research Articles

                Molecular medicine
                alzheimer's disease (ad),amyloid-β (aβ),bace1,bisecting glcnac,gnt-iii (mgat3)


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