Protective effect of N-glycan bisecting GlcNAc residues on β-amyloid production in Alzheimer's disease
Protective effect of N-glycan bisecting GlcNAc residues on β-amyloid production in Alzheimer's disease
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DOI：
10.1093/glycob/cwp152
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发表时间：
2010-01-01
期刊：
影响因子：
4.3
通讯作者：
Endo, Tamao
中科院分区：
文献类型：
--
作者：
Akasaka-Manya, Keiko;Manya, Hiroshi;Endo, Tamao
糖蛋白聚糖的改变常常会改变靶糖蛋白的各种特性，并导致多种疾病。在此，我们聚焦于淀粉样前体蛋白的N -聚糖，其裂解片段β -淀粉样蛋白被认为是导致阿尔茨海默病（AD）大部分病理变化的原因。我们先前确定了正常及突变型淀粉样前体蛋白（瑞典型和伦敦型）的N -聚糖结构。与正常淀粉样前体蛋白相比，突变型淀粉样前体蛋白含有更高比例的平分型GlcNAc残基。由于N -乙酰氨基葡萄糖基转移酶III（GnT - III）是负责合成平分型GlcNAc残基的糖基转移酶，本研究测量了AD患者大脑中GnT - III mRNA的表达水平。有趣的是，AD患者大脑中GnT - III mRNA的表达增加。此外，β -淀粉样蛋白处理可增加Neuro2a小鼠神经母细胞瘤细胞中GnT - III mRNA的表达。然后我们研究了平分型GlcNAc对β -淀粉样蛋白产生的影响。在GnT - III转染的细胞中，β -淀粉样蛋白40和β -淀粉样蛋白42均显著减少。当分析GnT - III转染细胞中的分泌酶活性时，发现α -分泌酶活性增加。综上所述，这些结果表明AD患者大脑中GnT - III的上调可能是一种适应性反应，以保护大脑免受更多β -淀粉样蛋白产生的影响。
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.