O-GlcNAcylation increases non-amyloidogenic processing of the amyloid-β precursor protein (APP)
2011
Jacobsen, Kristin T. | Iverfeldt, Kerstin
The amyloid-β precursor protein (APP) was shown to be O-GlcNAcylated 15years ago, but the effect of this modification on APP processing and formation of the Alzheimer’s disease associated amyloid-β (Aβ) peptide has so far not been investigated. Here, we demonstrate with pharmacological tools or siRNA that O-GlcNAcase and O-GlcNAc transferase regulate the level of O-GlcNAcylated APP. We also show that O-GlcNAcylation increases non-amyloidogenic α-secretase processing, resulting in increased levels of the neuroprotective sAPPα fragment and decreased Aβ secretion. Our results implicate O-GlcNAcylation as a potential therapeutic target for Alzheimer’s disease.
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