Curcumin Shows Neuroprotection against Oxidative Damage and Alters APP Processing Involving GSK-3β-mediated Protein O-GlcNAcylation

Abstract

Abstract Alzheimer’s disease (AD) is a neurodegenerative disease. Senile plaque is one of the pathological hallmarks in the AD brains, and Amyloid-β (Aβ) peptides are the main components in the senile plaque. The amyloidogenic cleavage of Amyloid-β precursor protein (APP) is a key event for Aβ product and further the formation of senile plaque. Recently, O-GlcNAcylation is suggested to regulate the pathways of APP cleavage. The neurotrophic effects of curcumin on AD rat and the mechanisms on APP O-GlcNAcylation and cleavage were investigated in this study. The hippocampal expression of human APPswe (the Swedish mutation of APP) resulted in the decline of learning and memory and the increase of neuronal oxidative damage and Aβ product. Curcumin relieved these AD-like symptoms and altered Aβ secretion. Like PugNAc (an inhibitor of O-GlcNAcase), curcumin upregulated the O-GlcNAcylation level of APP and switched APP cleavage from amyloidogenic pathway to nonamyloidogenic pathway. GSK-3β participated in APP O-GlcNAcylation and its silence through shRNA interference blocked curcumin-induced protein O-GlcNAcylation. These results indicated that curcumin downregulates APP cleavage of amyloidogenic pathway, involving GSK-3β-mediated protein O-GlcNAcylation. This study implied that GSK-3β is a potential target for regulating APP processing in AD treatment.