Excess APP O-glycosylation by GalNAc-T6 decreases A&bgr; production

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&bgr; 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&bgr; production. Transfection of GalNAc-T6 significantly reduced both A&bgr;1-40 and A&bgr;1-42 generation, but GalNAc-T1 and GalNAc-T4 only reduced A&bgr;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 &agr;-secretase and &bgr;-secretase was slightly altered in the transfected cells, but the activities of &agr;-secretase and &bgr;-secretase were not significantly altered. These data suggest that excess O-glycosylation on APP by GalNAc-T6 inhibits A&bgr; production.