Deposition of \u03b2-amyloid (A\u03b2) as senile plaques and disrupted glucose metabolism are two main characteristics of Alzheimer’s disease (AD). It is unknown, however, how these two processes are related in AD. Here we examined the relationship between O-GlcNAcylation, which is a glucose level-dependent post-translational modification that adds O-linked \u03b2-N-acetylglucosamine (O-GlcNAc) to proteins, and A\u03b2 production in a mouse model of AD carrying 5XFAD genes. We found that 1,2-dideoxy-2′-propyl-\u03b1-d-glucopyranoso-[2,1-D]-\u03942′-thiazoline (NButGT), a specific inhibitor of O-GlcNAcase, reduces A\u03b2 production by lowering \u03b3-secretase activity both in vitro and in vivo. We also found that O-GlcNAcylation takes place at the S708 residue of nicastrin, which is a component of \u03b3-secretase. Moreover, NButGT attenuated the accumulation of A\u03b2, neuroinflammation, and memory impairment in the 5XFAD mice. This is the first study to show the relationship between A\u03b2 generation and O-GlcNAcylation in vivo. These results suggest that O-GlcNAcylation may be a suitable therapeutic target for the treatment of AD.<\/p>\n