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

Scott A Yuzwa,Melissa L Woodward,Michael A Silverman,Neil V Watson,Xiaoyang Shan,Bryan A Jones,Gang Zhao,David J Vocadlo,Cheng-Xin Gong,Xiaojing Li,Yanping Zhu,Ernest J Mceachern

doi:10.1186/1750-1326-9-42

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.

Highlights

Amyloid plaques and neurofibrillary tangles (NFTs) are the defining pathological hallmarks of Alzheimer’s disease (AD)
Differing from the parent single transgenic models, TAPP mice brains contain both plaques and NFTs. These TAPP mice display enhanced tau pathology as compared to JNPL3 mice, suggesting that β-amyloid peptides accelerate the formation of NFTs [17], a proposal supported by other studies involving intracerebral injection of β-amyloid Aβ42 fibrils into P301L tau transgenic mice [18]
Here we have shown that Thiamet-G treatment of TAPP mice increases O-GlcNAc levels in the brain and completely prevents cognitive decline

Summary

Introduction

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, if O-GlcNAc can influence the formation of amyloid plaques in the presence of tau pathology. Mouse models that express human MAPT mutations, such as the P301L mutant expressing JNPL3 mice, do not produce neuritic plaques [16]. For this reason several groups have developed mouse models of AD that recapitulate both pathological features of AD. The TAPP mouse model is well suited to study therapeutic strategies that might impact neuritic plaques or NFT formation in a setting that captures these two synergistic pathologies

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