Quantitative proteomics identifies altered O-GlcNAcylation of structural, synaptic and memory-associated proteins in Alzheimer's disease

J Pathol. 2017 Sep;243(1):78-88. doi: 10.1002/path.4929. Epub 2017 Jul 28.


Protein modification by O-linked β-N-acetylglucosamine (O-GlcNAc) is emerging as an important factor in the pathogenesis of sporadic Alzheimer's disease (AD); however, detailed molecular characterization of this important protein post-translational modification at the proteome level has been highly challenging, owing to its low stoichiometry and labile nature. Herein, we report the most comprehensive, quantitative proteomics analysis for protein O-GlcNAcylation in postmortem human brain tissues with and without AD by the use of isobaric tandem mass tag labelling, chemoenzymatic photocleavage enrichment, and liquid chromatography coupled to mass spectrometry. A total of 1850 O-GlcNAc peptides covering 1094 O-GlcNAcylation sites were identified from 530 proteins in the human brain. One hundred and thirty-one O-GlcNAc peptides covering 81 proteins were altered in AD brains as compared with controls (q < 0.05). Moreover, alteration of O-GlcNAc peptide abundance could be attributed more to O-GlcNAcylation level than to protein level changes. The altered O-GlcNAcylated proteins belong to several structural and functional categories, including synaptic proteins, cytoskeleton proteins, and memory-associated proteins. These findings suggest that dysregulation of O-GlcNAcylation of multiple brain proteins may be involved in the development of sporadic AD. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: Alzheimer's disease; O-GlcNAcylation; isobaric labelling; mass spectrometry.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Alzheimer Disease / physiopathology
  • Alzheimer Disease / psychology
  • Autopsy
  • Biomarkers / metabolism
  • Brain / metabolism*
  • Brain / pathology
  • Brain / physiopathology
  • Case-Control Studies
  • Chromatography, Liquid
  • Glycosylation
  • Humans
  • Memory*
  • Nerve Tissue Proteins / metabolism*
  • Protein Processing, Post-Translational*
  • Proteomics* / methods
  • Reproducibility of Results
  • Synapses / metabolism*
  • Synapses / pathology
  • Synaptic Transmission*
  • Tandem Mass Spectrometry


  • Biomarkers
  • Nerve Tissue Proteins