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-translation 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 beta-amyloid peptide levels and decreased levels of amyloid plaques.
Conclusions:
This study indicates that increased O-GlcNAc can influence beta-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.
Author: Scott A YuzwaXiaoyang ShanBryan A JonesGang ZhaoMelissa L WoodwardXiaojing LiYanping ZhuErnest J McEachernMichael A SilvermanNeil V WatsonCheng-Xin GongDavid J Vocadlo
Credits/Source: Molecular Neurodegeneration 2014, 9:42
Published on: 2014-10-26
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