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

Excerpt

The amyloid-β precursor protein (APP) has been extensively studied, due to its role in Alzheimer’s disease (AD). Sequential proteolytic processing of APP, catalyzed by β- and γ-secretase, generates the neurotoxic peptide amyloid-β (Aβ), which accumulates in the brain and cause progressive neurodegeneration. However, APP is mainly processed through another pathway, where APP is cleaved by α- and γ-secretase, generating the secreted sAPPα fragment. Stimulation of α-secretase processing of APP constitutes an important therapeutical strategy, not only since it precludes the formation of Aβ, but also because the sAPPα fragment has been shown to have neuroprotective properties [1]. APP was the first plasma membrane protein shown to be O-GlcNAcylated [2], a dynamic post-translational modification involving the attachment of β-N-acetylglucosamine (GlcNAc) catalyzed by O-GlcNAc transferase and O-GlcNAcase. However, the consequences of APP O-GlcNAcylation have so far not been investigated. …