O-linked beta-N-acetylglucosaminidase inhibitor attenuates beta-amyloid plaque and rescues memory impairment

Deposition of beta-amyloid (A beta) 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 beta-N-acetylglucosamine (O-GlcNAc) to proteins, and A beta production in a mouse model of AD carrying 5XFAD genes. We found that 1,2-dideoxy-2'-propyl-alpha-D-glucopyranoso-[ 2,1-d]-Delta 2'-thiazoline (NButGT), a specific inhibitor of O-GlcNAcase, reduces A beta production by lowering gamma-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 gamma-secretase. Moreover, NButGT attenuated the accumulation of A beta, neuroinflammation, and memory impairment in the 5XFAD mice. This is the first study to show the relationship between A beta generation and O-GlcNAcylation in vivo. These results suggest that O-GlcNAcylation may be a suitable therapeutic target for the treatment of AD. (C) 2013 Elsevier Inc. All rights reserved.