Increasing O-GlcNAcylation Attenuates tau Hyperphosphorylation and Behavioral Impairment in rTg4510 Tauopathy Mice

by Selleckchem | Nov 12 2023

Background: Tauopathies such as Alzheimer's disease (AD) are characterized by abnormal hyperphosphorylation of the microtubule-associated protein tau (MAPT) aggregating into neurofibrillary tangles (NFTs). O-linked β-N-acetylglucosamine (O-GlcNAc) modifications have been suggested to regulate tau phosphorylation and aggregation and N-acetylglucosaminidase (OGA) removes GlcNAc moieties from proteins.

Methods: We investigated effects of the OGA inhibitor Thiamet G in rTg4510 primary neuronal cultures and in rTg4510 mice. The rTg4510 mice overexpress human tau harboring the P301L mutation and display an age-dependent progression of tau pathology including hyperphosphorylated tau species and NFTs. Aged rTg4510 mice exhibit a non-mnemonic behavioral defect involving a hyperactive phenotype that is associated with the progression of tau pathology.

Results: Thiamet G increased overall O-GlcNAc levels and crossed the blood brain barrier in rTg4510 mice. The free fraction of Thiamet G in the brain was 22-fold above the half maximal effective concentration (EC50) measured in rTg4510 primary neurons. Chronic Thiamet G treatment (18 weeks) initiated in young 6 week old rTg4510 mice increased brain O-GlcNAc levels and this corresponded with a significant reduction in soluble and insoluble hyperphosphorylated tau in aged 24 week old rTg4510 mice. Levels of normally phosphorylated P301L tau were not altered under these conditions. Reduction of hyperphosphorylated tau species by increased O-GlcNAcylation was associated with significant attenuation of hyperactivity in 24 week old rTg4510 mice.

Conclusions: Our findings support the pharmacological inhibition of OGA as a potential therapeutic approach for the treatment of AD and other tauopathies.

Comments:

The study you've provided investigates the potential therapeutic effects of an O-GlcNAcase (OGA) inhibitor called Thiamet G in the context of tauopathies, particularly Alzheimer's disease (AD). Here's a breakdown of the key findings and implications:

1. **Background on Tauopathies**: Tauopathies like Alzheimer's disease are characterized by the abnormal hyperphosphorylation of the microtubule-associated protein tau (MAPT), leading to the aggregation of tau into neurofibrillary tangles (NFTs). These NFTs are a hallmark of these diseases.

2. **O-GlcNAc Modifications**: O-GlcNAc modifications are a type of post-translational modification where N-acetylglucosamine (GlcNAc) moieties are added to proteins, including tau. These modifications are thought to play a role in regulating tau phosphorylation and aggregation.

3. **OGA Enzyme**: N-acetylglucosaminidase (OGA) is an enzyme responsible for removing GlcNAc moieties from proteins. In the context of tauopathies, inhibiting OGA could potentially increase O-GlcNAc levels on tau proteins.

4. **Study Methods**: The study used rTg4510 mice as a model for tau pathology. These mice overexpress human tau with the P301L mutation, leading to tau-related pathology that mimics aspects of AD. The researchers investigated the effects of Thiamet G, an OGA inhibitor, in primary neuronal cultures and in these mice.

5. **Results**:

a. **Thiamet G and O-GlcNAc Levels**: Thiamet G treatment increased O-GlcNAc levels in the brain. It also crossed the blood-brain barrier effectively in the rTg4510 mice.

b. **Reduction in Hyperphosphorylated Tau**: Chronic Thiamet G treatment in young mice resulted in increased brain O-GlcNAc levels and a significant reduction in both soluble and insoluble hyperphosphorylated tau in aged mice.

c. **No Change in Normally Phosphorylated Tau**: Interestingly, the levels of normally phosphorylated P301L tau were not altered by Thiamet G treatment.

d. **Behavioral Improvement**: The reduction of hyperphosphorylated tau species due to increased O-GlcNAcylation was associated with a significant attenuation of hyperactivity in the aged rTg4510 mice.

6. **Conclusions**: The study suggests that pharmacological inhibition of OGA, using Thiamet G, has the potential to be a therapeutic approach for the treatment of AD and other tauopathies. By increasing O-GlcNAcylation on tau proteins, it was possible to reduce the abnormal hyperphosphorylation and aggregation of tau, which are key pathological features of these diseases. Additionally, this reduction in tau pathology was associated with behavioral improvements in the mice.

These findings provide valuable insights into the potential role of O-GlcNAc modifications and OGA inhibition in the development of therapies for tauopathies, including Alzheimer's disease. Further research and clinical trials would be needed to validate the effectiveness and safety of OGA inhibitors as a treatment approach for humans with these diseases.