期刊
MOLECULAR NEURODEGENERATION
卷 9, 期 -, 页码 -出版社
BMC
DOI: 10.1186/1750-1326-9-42
关键词
tau; Amyloid precursor protein; O-GlcNAc; Thiamet-G
资金
- National Institute on Aging/National Institutes of Health [R21AG031969, R01AG027429]
- U.S. Alzheimer's Association [IIRG-10-170405]
- Natural Sciences and Engineering Research Council of Canada (NSERC) [00194522]
- NSERC [327100-06]
- Canadian Institutes of Health Research (CIHR) [90396]
- SFU
- NSERC
- NATIONAL INSTITUTE ON AGING [R01AG027429, R21AG031969] Funding Source: NIH RePORTER
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 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.
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