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

• Published in: Molecular neurodegeneration Vol. 9; no. 1; p. 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: Journal Article
• Language: English
• Published: England BioMed Central Ltd 26.10.2014; BioMed Central
• 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
• ISSN: 1750-1326; 1750-1326
• DOI: 10.1186/1750-1326-9-42

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.