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Inhibition of O-GlcNAcase leads to elevation of O-GlcNAc tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice

Overview of attention for article published in Molecular Neurodegeneration, May 2017
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  • In the top 25% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (83rd percentile)

Mentioned by

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1 news outlet
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3 tweeters

Citations

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32 Dimensions

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42 Mendeley
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Title
Inhibition of O-GlcNAcase leads to elevation of O-GlcNAc tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice
Published in
Molecular Neurodegeneration, May 2017
DOI 10.1186/s13024-017-0181-0
Pubmed ID
Authors

Nicholas B. Hastings, Xiaohai Wang, Lixin Song, Brent D. Butts, Diane Grotz, Richard Hargreaves, J. Fred Hess, Kwok-Lam Karen Hong, Cathy Ruey-Ruey Huang, Lynn Hyde, Maureen Laverty, Julie Lee, Diane Levitan, Sherry X. Lu, Maureen Maguire, Veeravan Mahadomrongkul, Ernest J. McEachern, Xuesong Ouyang, Thomas W. Rosahl, Harold Selnick, Michaela Stanton, Giuseppe Terracina, David J. Vocadlo, Ganfeng Wang, Joseph L. Duffy, Eric M. Parker, Lili Zhang

Abstract

Hyperphosphorylation of microtubule-associated protein tau is a distinct feature of neurofibrillary tangles (NFTs) that are the hallmark of neurodegenerative tauopathies. O-GlcNAcylation is a lesser known post-translational modification of tau that involves the addition of N-acetylglucosamine onto serine and threonine residues. Inhibition of O-GlcNAcase (OGA), the enzyme responsible for the removal of O-GlcNAc modification, has been shown to reduce tau pathology in several transgenic models. Clarifying the underlying mechanism by which OGA inhibition leads to the reduction of pathological tau and identifying translatable measures to guide human dosing and efficacy determination would significantly facilitate the clinical development of OGA inhibitors for the treatment of tauopathies. Genetic and pharmacological approaches are used to evaluate the pharmacodynamic response of OGA inhibition. A panel of quantitative biochemical assays is established to assess the effect of OGA inhibition on pathological tau reduction. A "click" chemistry labeling method is developed for the detection of O-GlcNAcylated tau. Substantial (>80%) OGA inhibition is required to observe a measurable increase in O-GlcNAcylated proteins in the brain. Sustained and substantial OGA inhibition via chronic treatment with Thiamet G leads to a significant reduction of aggregated tau and several phosphorylated tau species in the insoluble fraction of rTg4510 mouse brain and total tau in cerebrospinal fluid (CSF). O-GlcNAcylated tau is elevated by Thiamet G treatment and is found primarily in the soluble 55 kD tau species, but not in the insoluble 64 kD tau species thought as the pathological entity. The present study demonstrates that chronic inhibition of OGA reduces pathological tau in the brain and total tau in the CSF of rTg4510 mice, most likely by directly increasing O-GlcNAcylation of tau and thereby maintaining tau in the soluble, non-toxic form by reducing tau aggregation and the accompanying panoply of deleterious post-translational modifications. These results clarify some conflicting observations regarding the effects and mechanism of OGA inhibition on tau pathology, provide pharmacodynamic tools to guide human dosing and identify CSF total tau as a potential translational biomarker. Therefore, this study provides additional support to develop OGA inhibitors as a treatment for Alzheimer's disease and other neurodegenerative tauopathies.

Twitter Demographics

The data shown below were collected from the profiles of 3 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 42 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United States 1 2%
France 1 2%
Unknown 40 95%

Demographic breakdown

Readers by professional status Count As %
Researcher 13 31%
Professor > Associate Professor 7 17%
Student > Ph. D. Student 6 14%
Student > Bachelor 4 10%
Student > Doctoral Student 2 5%
Other 5 12%
Unknown 5 12%
Readers by discipline Count As %
Agricultural and Biological Sciences 9 21%
Neuroscience 9 21%
Chemistry 6 14%
Unspecified 2 5%
Biochemistry, Genetics and Molecular Biology 2 5%
Other 5 12%
Unknown 9 21%

Attention Score in Context

This research output has an Altmetric Attention Score of 11. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 23 September 2019.
All research outputs
#1,569,992
of 14,051,004 outputs
Outputs from Molecular Neurodegeneration
#177
of 589 outputs
Outputs of similar age
#44,630
of 265,483 outputs
Outputs of similar age from Molecular Neurodegeneration
#2
of 4 outputs
Altmetric has tracked 14,051,004 research outputs across all sources so far. Compared to these this one has done well and is in the 88th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 589 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 8.8. This one has gotten more attention than average, scoring higher than 69% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 265,483 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 83% of its contemporaries.
We're also able to compare this research output to 4 others from the same source and published within six weeks on either side of this one. This one has scored higher than 2 of them.