Protective effect of N-glycan bisecting GlcNAc residues on beta-amyloid production in Alzheimer's disease.
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.
Department of Glycobiology, Tokyo Metropolitan Institute of Gerontology, Foundation for Research on Aging and Promotion of Human Welfare, Itabashi-ku, Tokyo 173-0015, Japan.
Keiko
K
Akasaka-Manya
Hiroshi
H
Manya
Yoko
Y
Sakurai
Boguslaw S
BS
Wojczyk
Yasunori
Y
Kozutsumi
Yuko
Y
Saito
Naoyuki
N
Taniguchi
Shigeo
S
Murayama
Steven L
SL
Spitalnik
Tamao
T
Endo
D000375:Aging; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D017351:N-Acetylglucosaminyltransferases / Q000737:chemistry*; D011134:Polysaccharides / Q000737:chemistry*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
D016229:Amyloid beta-Peptides; D011134:Polysaccharides; D012333:RNA, Messenger; D017351:N-Acetylglucosaminyltransferases; C037649:N-acetyllactosaminide beta-1,6-N-acetylglucosaminyltransferase