Pharmacological Inhibition of O-GlcNAcase (OGA) Prevents Cognitive Decline and Amyloid Plaque Formation in Bigenic Tau/APP Mutant Mice

Resource type
Date created
2014
Authors/Contributors
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.
Document
Published as
Molecular Neurodegeneration 2014, 9:42 doi:10.1186/1750-1326-9-42The electronic version of this article is the complete one and can be found online at: http://www.molecularneurodegeneration.com/content/9/1/42
Publication title
Molecular Neurodegeneration
Document title
Pharmacological Inhibition of O-GlcNAcase (OGA) Prevents Cognitive Decline and Amyloid Plaque Formation in Bigenic Tau/APP Mutant Mice
Date
2014
Volume
9
Publisher DOI
10.1186/1750-1326-9-42
Copyright statement
Copyright is held by the author(s).
Scholarly level
Peer reviewed?
Yes
Language
Attachment Size
1750-1326-9-42.pdf 1.35 MB