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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2014

Open Access 01-12-2014 | Research article

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

Authors: Scott A Yuzwa, Xiaoyang Shan, Bryan A Jones, Gang Zhao, Melissa L Woodward, Xiaojing Li, Yanping Zhu, Ernest J McEachern, Michael A Silverman, Neil V Watson, Cheng-Xin Gong, David J Vocadlo

Published in: Molecular Neurodegeneration | Issue 1/2014

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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.
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Metadata
Title
Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice
Authors
Scott A Yuzwa
Xiaoyang Shan
Bryan A Jones
Gang Zhao
Melissa L Woodward
Xiaojing Li
Yanping Zhu
Ernest J McEachern
Michael A Silverman
Neil V Watson
Cheng-Xin Gong
David J Vocadlo
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2014
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/1750-1326-9-42

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