title: Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice.
abstract: BACKGROUND
  Amyloid plaques and neurofibrillary tangles (NFTs) are the defining pathological hallmarks of Alzheimer's disease (AD). Increasing the quantity of the O-linked N-acetylglucosamine (O-GlcNAc) post-translational modification of nuclear and cytoplasmic proteins slows neurodegeneration and blocks the formation of NFTs in a tauopathy mouse model. It remains unknown, however, if O-GlcNAc can influence the formation of amyloid plaques in the presence of tau pathology.
  
  
  RESULTS
  We treated double transgenic TAPP mice, which express both mutant human tau and amyloid precursor protein (APP), with a highly selective orally bioavailable inhibitor of the enzyme responsible for removing O-GlcNAc (OGA) to increase O-GlcNAc in the brain. We find that increased O-GlcNAc levels block cognitive decline in the TAPP mice and this effect parallels decreased β-amyloid peptide levels and decreased levels of amyloid plaques.
  
  
  CONCLUSIONS
  This study indicates that increased O-GlcNAc can influence β-amyloid pathology in the presence of tau pathology. The findings provide good support for OGA as a promising therapeutic target to alter disease progression in Alzheimer disease.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Yuzwa
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Shan
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Jones
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Woodward
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Li
authors.forename: Yanping
authors.initials: Y
authors.lastname: Zhu
authors.forename: Ernest J
authors.initials: EJ
authors.lastname: McEachern
authors.forename: Michael A
authors.initials: MA
authors.lastname: Silverman
authors.forename: Neil V
authors.initials: NV
authors.lastname: Watson
authors.forename: Cheng-Xin
authors.initials: CX
authors.lastname: Gong
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Dr, Burnaby, BC V5A 1S6, Canada. dvocadlo@sfu.ca.
authors.forename: David J
authors.initials: DJ
authors.lastname: Vocadlo
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000473:pathology*; D016875:tau Proteins / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D016875:tau Proteins; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase