[HTML][HTML] Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice
Molecular neurodegeneration, 2014•Springer
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 …
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 …
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 β-amyloid peptide levels and decreased levels of amyloid plaques.
Conclusions
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.
Springer