PMID- 24759912
OWN - NLM
STAT- MEDLINE
DCOM- 20150514
LR  - 20190828
IS  - 1460-4744 (Electronic)
IS  - 0306-0012 (Linking)
VI  - 43
IP  - 19
DP  - 2014 Oct 7
TI  - O-GlcNAc and neurodegeneration: biochemical mechanisms and potential roles in 
      Alzheimer's disease and beyond.
PG  - 6839-58
LID - 10.1039/c4cs00038b [doi]
AB  - Alzheimer disease (AD) is a growing problem for aging populations worldwide. 
      Despite significant efforts, no therapeutics are available that stop or slow 
      progression of AD, which has driven interest in the basic causes of AD and the 
      search for new therapeutic strategies. Longitudinal studies have clarified that 
      defects in glucose metabolism occur in patients exhibiting Mild Cognitive 
      Impairment (MCI) and glucose hypometabolism is an early pathological change 
      within AD brain. Further, type 2 diabetes mellitus (T2DM) is a strong risk factor 
      for the development of AD. These findings have stimulated interest in the 
      possibility that disrupted glucose regulated signaling within the brain could 
      contribute to the progression of AD. One such process of interest is the addition 
      of O-linked N-acetylglucosamine (O-GlcNAc) residues onto nuclear and cytoplasmic 
      proteins within mammals. O-GlcNAc is notably abundant within brain and is present 
      on hundreds of proteins including several, such as tau and the amyloid precursor 
      protein, which are involved in the pathophysiology AD. The cellular levels of 
      O-GlcNAc are coupled to nutrient availability through the action of just two 
      enzymes. O-GlcNAc transferase (OGT) is the glycosyltransferase that acts to 
      install O-GlcNAc onto proteins and O-GlcNAcase (OGA) is the glycoside hydrolase 
      that acts to remove O-GlcNAc from proteins. Uridine 
      5'-diphosphate-N-acetylglucosamine (UDP-GlcNAc) is the donor sugar substrate for 
      OGT and its levels vary with cellular glucose availability because it is 
      generated from glucose through the hexosamine biosynthetic pathway (HBSP). Within 
      the brains of AD patients O-GlcNAc levels have been found to be decreased and 
      aggregates of tau appear to lack O-GlcNAc entirely. Accordingly, glucose 
      hypometabolism within the brain may result in disruption of the normal functions 
      of O-GlcNAc within the brain and thereby contribute to downstream 
      neurodegeneration. While this hypothesis remains largely speculative, recent 
      studies using different mouse models of AD have demonstrated the protective 
      benefit of pharmacologically increased brain O-GlcNAc levels. In this review we 
      summarize the state of knowledge in the area of O-GlcNAc as it pertains to AD 
      while also addressing some of the basic biochemical roles of O-GlcNAc and how 
      these might contribute to protecting against AD and other neurodegenerative 
      diseases.
FAU - Yuzwa, Scott A
AU  - Yuzwa SA
AD  - Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 
      University Dr, Burnaby, BC V5A 1S6, Canada.
FAU - Vocadlo, David J
AU  - Vocadlo DJ
LA  - eng
GR  - MOP-123341/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20140424
PL  - England
TA  - Chem Soc Rev
JT  - Chemical Society reviews
JID - 0335405
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (tau Proteins)
RN  - EC 2.3.1.48 (Histone Acetyltransferases)
RN  - EC 2.4.1.- (N-Acetylglucosaminyltransferases)
RN  - EC 2.4.1.- (O-GlcNAc transferase)
RN  - EC 3.2.1.169 (OGA protein, human)
RN  - EC 3.2.1.35 (Hyaluronoglucosaminidase)
RN  - V956696549 (Acetylglucosamine)
SB  - IM
MH  - Acetylglucosamine/chemistry/*metabolism
MH  - Alzheimer Disease/metabolism/*pathology
MH  - Amyloid beta-Peptides/chemistry/metabolism
MH  - Animals
MH  - Antigens, Neoplasm/metabolism
MH  - Histone Acetyltransferases/antagonists & inhibitors/metabolism
MH  - Humans
MH  - Hyaluronoglucosaminidase/antagonists & inhibitors/metabolism
MH  - N-Acetylglucosaminyltransferases/antagonists & inhibitors/metabolism
MH  - Neurodegenerative Diseases/metabolism/*pathology
MH  - tau Proteins/chemistry/genetics/metabolism
EDAT- 2014/04/25 06:00
MHDA- 2015/05/15 06:00
CRDT- 2014/04/25 06:00
PHST- 2014/04/25 06:00 [entrez]
PHST- 2014/04/25 06:00 [pubmed]
PHST- 2015/05/15 06:00 [medline]
AID - 10.1039/c4cs00038b [doi]
PST - ppublish
SO  - Chem Soc Rev. 2014 Oct 7;43(19):6839-58. doi: 10.1039/c4cs00038b. Epub 2014 Apr 
      24.