Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice

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 t...

Full description

Saved in:
Bibliographic Details
Published in:Molecular neurodegeneration 2014-10, Vol.9 (1), p.42-42, Article 42
Main Authors: Yuzwa, Scott A, Shan, Xiaoyang, Jones, Bryan A, Zhao, Gang, Woodward, Melissa L, Li, Xiaojing, Zhu, Yanping, McEachern, Ernest J, Silverman, Michael A, Watson, Neil V, Gong, Cheng-Xin, Vocadlo, David J
Format: Article
Language:English
Subjects:
Advertising executives
Alzheimer Disease - enzymology
Alzheimer Disease - pathology
Alzheimer's disease
Amyloid beta-Protein Precursor - genetics
Analysis
Animal cognition
Animals
Blotting, Western
Cognitive ability
Disease Models, Animal
Enzyme Inhibitors - pharmacology
Enzyme-Linked Immunosorbent Assay
Female
Health aspects
Humans
Immunohistochemistry
Maze Learning - drug effects
Medical research
Medicine, Experimental
Mice
Mice, Transgenic
Mutation
N-Acetylglucosaminyltransferases - metabolism
Pathology
Peptides
Plaque, Amyloid - pathology
Proteins
Rodents
Studies
tau Proteins - genetics
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. 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. 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.
ISSN:1750-1326
1750-1326
DOI:10.1186/1750-1326-9-42