title: Increased O-GlcNAc levels correlate with decreased O-GlcNAcase levels in Alzheimer disease brain.
abstract: The potential role of the posttranslational modification of proteins with O-linked N-acetyl-β-d-glucosamine (O-GlcNAc) in the pathogenesis of Alzheimer disease (AD) has been studied extensively, yet the exact function of O-GlcNAc in AD remains elusive. O-GlcNAc cycling is facilitated by only two highly conserved enzymes: O-GlcNAc transferase (OGT) catalyzes the addition, while O-GlcNAcase (OGA) catalyzes the removal of GlcNAc from proteins. Studies analyzing global O-GlcNAc levels in AD brain have produced inconsistent results and the reasons for altered O-GlcNAcylation in AD are still poorly understood. In this study, we show a 1.2-fold increase in cytosolic protein O-GlcNAc modification in AD brain when compared to age-matched controls. Interestingly, O-GlcNAc changes seem to be attributable to differential modification of a few individual proteins. While our finding of augmented O-GlcNAcylation concurs with some reports, it is contrary to others demonstrating decreased O-GlcNAc levels in AD brain. These conflicting results emphasize the need for further studies providing conclusive evidence on the subject of O-GlcNAcylation in AD. We further demonstrate that, while OGT protein levels are unaffected in AD, OGA protein levels are significantly decreased to 75% of those in control samples. In addition, augmented protein O-GlcNAc modification correlates to decreased OGA protein levels in AD subjects. While OGA inhibitors are already being tested for AD treatment, our results provide a strong indication that the general subject of O-GlcNAcylation and specifically its regulation by OGA and OGT in AD need further investigation to conclusively elucidate its potential role in AD pathogenesis and treatment.
authors.affiliation: Department of Biochemistry, Institute of Animal Sciences, University of Bonn, 53115 Bonn, Germany; Department of Chemistry, Center of Membrane Sciences, University of Kentucky, Lexington, KY 40506, USA. Electronic address: forster@uni-bonn.de.
authors.forename: Sarah
authors.initials: S
authors.lastname: Förster
authors.affiliation: Department of Chemistry, Center of Membrane Sciences, University of Kentucky, Lexington, KY 40506, USA. Electronic address: andrew.welleford@uky.edu.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Welleford
authors.affiliation: Department of Chemistry, Center of Membrane Sciences, University of Kentucky, Lexington, KY 40506, USA. Electronic address: judy.triplett@uky.edu.
authors.forename: Judy C
authors.initials: JC
authors.lastname: Triplett
authors.affiliation: Department of Chemistry, Center of Membrane Sciences, University of Kentucky, Lexington, KY 40506, USA. Electronic address: Rukhsana.Sultana@UTSouthwestern.edu.
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Sultana
authors.affiliation: Department of Biochemistry, Institute of Animal Sciences, University of Bonn, 53115 Bonn, Germany. Electronic address: schmitz@uni-bonn.de.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schmitz
authors.affiliation: Department of Chemistry, Center of Membrane Sciences, University of Kentucky, Lexington, KY 40506, USA; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA. Electronic address: dabcns@uky.edu.
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008297:Male; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism*
chemical_list: D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D000117:Acetylglucosamine
keywords: Alzheimer disease; O-GlcNAc; O-GlcNAcase