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Updated: Mar 22, 2026
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
O-GlcNAcylation: A regulator of tau pathology and neurodegeneration
Cheng-Xin Gong1, Fei Liu1, Khalid Iqbal1
1Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
Abstract:
O-GlcNAcylation is the posttranslational modification of intracellular proteins by O-linked β-N-acetylglucosamine (O-GlcNAc). The discovery of O-GlcNAc modification of tau and its impact on tau phosphorylation has attracted recent research interest in O-GlcNAc studies in the Alzheimer's disease (AD) field. Modification of proteins by O-GlcNAc occurs extensively in the brain. The expressions and activities of the enzymes catalyzing O-GlcNAc cycling are several-fold higher in the brain than in the peripheral tissues. The O-GlcNAcylation levels of brain proteins including tau are decreased in AD brain, probably due to decreased brain glucose metabolism. The reduction of brain O-GlcNAcylation appears to mediate the molecular mechanism by which decreased brain glucose metabolism contributes to neurodegeneration. Studies on mouse models of tauopathies suggest a neuroprotective role of pharmacological elevation of brain O-GlcNAc, which could potentially be a promising approach for treating AD and other neurodegenerative diseases.
Insights
Alzheimer's disease (AD) involves decreased O-linked β-N-acetylglucosamine (O-GlcNAc) brain modification, impacting tau protein. Elevating O-GlcNAc shows neuroprotective potential for treating AD and neurodegenerative diseases.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- O-GlcNAcylation is a crucial intracellular protein modification by O-linked β-N-acetylglucosamine (O-GlcNAc).
- O-GlcNAc modification of tau protein and its influence on tau phosphorylation are gaining attention in Alzheimer's disease (AD) research.
- Brain O-GlcNAcylation is significantly higher than in peripheral tissues, with key enzymes showing increased activity.
Purpose of the Study:
- To investigate the role of O-GlcNAcylation in Alzheimer's disease pathogenesis.
- To explore the relationship between brain glucose metabolism, O-GlcNAcylation levels, and neurodegeneration.
- To evaluate the therapeutic potential of enhancing brain O-GlcNAc levels for AD treatment.
Main Methods:
- Analysis of O-GlcNAcylation levels in postmortem Alzheimer's disease brain tissue.
- Examination of enzyme expression and activity involved in O-GlcNAc cycling in the brain.
- Studies utilizing mouse models of tauopathies to assess the effects of pharmacological O-GlcNAc elevation.
Main Results:
- O-GlcNAcylation levels of brain proteins, including tau, are reduced in Alzheimer's disease brains.
- Decreased brain glucose metabolism is associated with reduced O-GlcNAcylation and contributes to neurodegeneration.
- Pharmacological elevation of brain O-GlcNAc demonstrates neuroprotective effects in mouse models of tauopathies.
Conclusions:
- Reduced brain O-GlcNAcylation, linked to impaired glucose metabolism, is a key mechanism in Alzheimer's disease neurodegeneration.
- Targeting and enhancing O-GlcNAcylation presents a promising therapeutic strategy for Alzheimer's disease and other neurodegenerative disorders.
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