Journal
JOURNAL OF BIOCHEMISTRY
Volume 161, Issue 1, Pages 99-111Publisher
OXFORD UNIV PRESS
DOI: 10.1093/jb/mvw056
Keywords
Alzheimer's disease; amyloid precursor protein; GalNAc-T; O-glycan
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Funding
- Japan Society for Promotion Science (JSPS) [JP 26460090, JP 19790244]
- Samuro Kakiuchi Memorial Research Award for Young Scientists
- Grants-in-Aid for Scientific Research [26460090, 26117004, 16H06277] Funding Source: KAKEN
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Alterations of the structure and/or amount of glycans present on proteins are associated with many diseases. We previously demonstrated that changes in N-glycans alter A beta production. In the present study, we focused on the relationship between Alzheimer's disease (AD) and O-glycan, another type of glycan. The UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferase (GalNAc-T) family functions in the first step of mucin-type O-glycan synthesis. Analysis of the expression of GalNAc-Ts in the human brain using real-time PCR revealed that the expression of several GalNAc-Ts was altered with sporadic AD progression. Three of these GalNAc-Ts (GalNAc-T1, GalNAc-T4 and GalNAc-T6) were transfected into HEK293T cells to examine their impact on A beta production. Transfection of GalNAc-T6 significantly reduced both A beta 1-40 and A beta 1-42 generation, but GalNAc-T1 and GalNAc-T4 only reduced A beta 1-40 generation. Although these three GalNAc-Ts exhibited enzymatic activities on soluble amyloid precursor protein (APP), the GalNAc transferase activity of GalNAc-T6 to APP was most prominent. The expression of alpha-secretase and p-secretase was slightly altered in the transfected cells, but the activities of alpha-secretase and beta-secretase were not significantly altered. These data suggest that excess O-glycosylation on APP by GalNAc-T6 inhibits AD production.
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