Glycobiology Advance Access originally published online on September 23, 2009
Glycobiology 2010 20(1):99-106; doi:10.1093/glycob/cwp152
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Protective effect of N-glycan bisecting GlcNAc residues on β-amyloid production in Alzheimer's disease
2 Department of Glycobiology, Tokyo Metropolitan Institute of Gerontology, Foundation for Research on Aging and Promotion of Human Welfare, Itabashi-ku, Tokyo 173-0015, Japan
3 Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA
4 Laboratory of Membrane Biochemistry and Biophysics, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto, 606-8501
5 Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Foundation for Research on Aging and Promotion of Human Welfare, Itabashi-ku, Tokyo 173-0015
6 Department of Disease Glycomics, The Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka 565-0047, Japan
1 To whom correspondence should be addressed: Tel: +81-3-3964-3241 ext. 3080; Fax: +81-3-3579-4776; e-mail: endo{at}tmig.or.jp
Received on August 4, 2009; revised on September 14, 2009; accepted on September 15, 2009
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, β-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, β-amyloid treatment increased GnT-III mRNA expression in Neuro2a mouse neuroblastoma cells. We then examined the influence of bisecting GlcNAc on the production of β-amyloid. Both β-amyloid 40 and β-amyloid 42 were significantly decreased in GnT-III-transfected cells. When secretase activities were analyzed in GnT-III transfectant cells, 
-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 β-amyloid production.
Key words: Alzheimer’s disease / amyloid precursor protein / bisecting GlcNAc / N-glycan