Affiliation: | 1.Department of Molecular Biology and Biochemistry,Simon Fraser University,Burnaby,Canada;2.Department of Neurosciences and Mental Health,The Hospital for Sick Children,Toronto,Canada;3.Department of Psychology,Simon Fraser University,Burnaby,Canada;4.Department of Neurochemistry,New York State Institute for Basic Research in Developmental Disabilities,Staten Island,USA;5.Department of Biological Sciences,Simon Fraser University,Burnaby,Canada;6.Department of Chemistry,Simon Fraser University,Burnaby,Canada;7.Alectos Therapeutics Inc.,Burnaby,Canada |
Abstract: | BackgroundAmyloid 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.ResultsWe 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.ConclusionsThis 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. |