O-GlcNAcylation increases non-amyloidogenic processing of the amyloid-β precursor protein (APP)

Abstract

Here, we show that O-GlcNAcase and O-GlcNAc transferase regulate the level of APP that is immunoprecipitated with O-GlcNAc antibody in human neuroblastoma SH-SY5Y cells. We also show that O-GlcNAcylation increases a-secretase processing, resulting in increased levels of the neuroprotective sAPPa fragment and decreased Ab secretion. The proteolytic processing of the APP homologue, APLP2, remained unchanged in response to increased O-GlcNAcylation. Furthermore, the effect of O-GlcNacylation on APP processing seems to be specific for neuron-like cells, since the levels of sAPPa from the human embryonic kidney cell-line HEK293 remains unchanged in response to inhibition of O-GlcNAcase, whereas the neuroblastoma cell-line SK-N-AS show increased sAPPa levels, but not to the same extent as in SH-SY5Y cells.