Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice
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| Authors: | Yuzwa, SA; Shan, XY; Jones, BA; Zhao, G; Woodward, ML; Li, XJ; Zhu, YP; McEachern, EJ; Silverman, MA; Watson, NV; Gong, CX; Vocadlo, DJ |
| Year: | 2014 |
| Journal: | Molecular Neurodegeneration 9 Article Link (DOI) PubMed |
| 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 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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