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

Chaeyoung Kim, Dong Woo Nam, Sang Yoon Park, Hyundong Song, Hyun Seok Hong, Jung Hyun Boo, Eun Sun Jung, Yoonhee Kim, Ju Yuel Baek, Kwan Soo Kim, Jin Won Cho, Inhee Mook-Jung

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58 Citations (Scopus)

Abstract

Deposition of β-amyloid (Aβ) 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 β-N-acetylglucosamine (O-GlcNAc) to proteins, and Aβ production in a mouse model of AD carrying 5XFAD genes. We found that 1,2-dideoxy-2'-propyl-α- d-glucopyranoso-[2,1-d]-δ2'-thiazoline (NButGT), a specific inhibitor of O-GlcNAcase, reduces Aβ production by lowering γ-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 γ-secretase. Moreover, NButGT attenuated the accumulation of Aβ, neuroinflammation, and memory impairment in the 5XFAD mice. This is the first study to show the relationship between Aβ generation and O-GlcNAcylation in vivo. These results suggest that O-GlcNAcylation may be a suitable therapeutic target for the treatment of AD.

Original languageEnglish
Pages (from-to)275-285
Number of pages11
JournalNeurobiology of Aging
Volume34
Issue number1
DOIs
Publication statusPublished - 2013 Jan 1

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Ageing
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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    Kim, C., Nam, D. W., Park, S. Y., Song, H., Hong, H. S., Boo, J. H., Jung, E. S., Kim, Y., Baek, J. Y., Kim, K. S., Cho, J. W., & Mook-Jung, I. (2013). O-linked β-N-acetylglucosaminidase inhibitor attenuates β-amyloid plaque and rescues memory impairment. Neurobiology of Aging, 34(1), 275-285. https://doi.org/10.1016/j.neurobiolaging.2012.03.001