Protective effect of N-glycan bisecting GlcNAc residues on β-amyloid production in Alzheimer's disease

被引:78
作者
Akasaka-Manya, Keiko [1 ]
Manya, Hiroshi [1 ]
Sakurai, Yoko [1 ]
Wojczyk, Boguslaw S. [2 ]
Kozutsumi, Yasunori [3 ]
Saito, Yuko [4 ]
Taniguchi, Naoyuki [5 ]
Murayama, Shigeo [4 ]
Spitalnik, Steven L. [2 ]
Endo, Tamao [1 ]
机构
[1] Tokyo Metropolitan Inst Gerontol, Dept Glycobiol, Fdn Res Aging & Promot Human Welf, Itabashi Ku, Tokyo 1730015, Japan
[2] Columbia Univ, Med Ctr, Dept Pathol & Cell Biol, New York, NY 10032 USA
[3] Kyoto Univ, Lab Membrane Biochem & Biophys, Grad Sch Biostudies, Sakyo Ku, Kyoto 6068501, Japan
[4] Tokyo Metropolitan Inst Gerontol, Fdn Res Aging & Promot Human Welf, Dept Neuropathol, Itabashi Ku, Tokyo 1730015, Japan
[5] Osaka Univ, Dept Dis Glycom, Inst Sci & Ind Res, Osaka 5650047, Japan
基金
日本学术振兴会;
关键词
Alzheimer's disease; amyloid precursor protein; bisecting GlcNAc; N-glycan; NECROSIS-FACTOR-ALPHA; CONVERTING-ENZYME TACE; PRECURSOR PROTEIN APP; LINKED SUGAR CHAINS; INTRACELLULAR MATURATION; GLYCOPROTEIN-SYNTHESIS; CELLULAR MECHANISMS; GAMMA-SECRETASE; GLYCOSYLATION; OLIGOSACCHARIDES;
D O I
10.1093/glycob/cwp152
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Alteration of glycoprotein glycans often changes various properties of the target glycoprotein and contributes to a wide variety of diseases. Here, we focused on the N-glycans of amyloid precursor protein whose cleaved fragment, beta-amyloid, is thought to cause much of the pathology of Alzheimer's disease (AD). We previously determined the N-glycan structures of normal and mutant amyloid precursor proteins (the Swedish type and the London type). In comparison with normal amyloid precursor protein, mutant amyloid precursor proteins had higher contents of bisecting GlcNAc residues. Because N-acetylglucosaminyltransferase III (GnT-III) is the glycosyltransferase responsible for synthesizing a bisecting GlcNAc residue, the current report measured GnT-III mRNA expression levels in the brains of AD patients. Interestingly, GnT-III mRNA expression was increased in AD brains. Furthermore, beta-amyloid treatment increased GnT-III mRNA expression in Neuro2a mouse neuroblastoma cells. We then examined the influence of bisecting GlcNAc on the production of beta-amyloid. Both beta-amyloid 40 and beta-amyloid 42 were significantly decreased in GnT-III-transfected cells. When secretase activities were analyzed in GnT-III transfectant cells, alpha-secretase activity was increased. Taken together, these results suggest that upregulation of GnT-III in AD brains may represent an adaptive response to protect them from additional beta-amyloid production.
引用
收藏
页码:99 / 106
页数:8
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