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Evaluation of the brain-penetrant microtubule-stabilizing agent, dictyostatin, in the PS19 tau transgenic mouse model of tauopathy

Overview of attention for article published in Acta Neuropathologica Communications, September 2016
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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)
  • Above-average Attention Score compared to outputs of the same age and source (55th percentile)

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Title
Evaluation of the brain-penetrant microtubule-stabilizing agent, dictyostatin, in the PS19 tau transgenic mouse model of tauopathy
Published in
Acta Neuropathologica Communications, September 2016
DOI 10.1186/s40478-016-0378-4
Pubmed ID
Authors

Vishruti Makani, Bin Zhang, Heeoon Han, Yuemang Yao, Pierrik Lassalas, Kevin Lou, Ian Paterson, Virginia M. Y. Lee, John Q. Trojanowski, Carlo Ballatore, Amos B. Smith, Kurt R. Brunden

Abstract

Neurodegenerative disorders referred to as tauopathies, which includes Alzheimer's disease (AD), are characterized by insoluble deposits of the tau protein within neuron cell bodies and dendritic processes in the brain. Tau is normally associated with microtubules (MTs) in axons, where it provides MT stabilization and may modulate axonal transport. However, tau becomes hyperphosphorylated and dissociates from MTs in tauopathies, with evidence of reduced MT stability and defective axonal transport. This has led to the hypothesis that MT-stabilizing drugs may have potential for the treatment of tauopathies. Prior studies demonstrated that the brain-penetrant MT-stabilizing drug, epothilone D, had salutary effects in transgenic (Tg) mouse models of tauopathy, improving MT density and axonal transport, while reducing axonal dystrophy. Moreover, epothilone D enhanced cognitive performance and decreased hippocampal neuron loss, with evidence of reduced tau pathology. To date, epothilone D has been the only non-peptide small molecule MT-stabilizing agent to be evaluated in Tg tau mice. Herein, we demonstrate the efficacy of another small molecule brain-penetrant MT-stabilizing agent, dictyostatin, in the PS19 tau Tg mouse model. Although dictyostatin was poorly tolerated at once-weekly doses of 1 mg/kg or 0.3 mg/kg, likely due to gastrointestinal (GI) complications, a dictyostatin dose of 0.1 mg/kg was better tolerated, such that the majority of 6-month old PS19 mice, which harbor a moderate level of brain tau pathology, completed a 3-month dosing study without evidence of significant body weight loss. Importantly, as previously observed with epothilone D, the dictyostatin-treated PS19 mice displayed improved MT density and reduced axonal dystrophy, with a reduction of tau pathology and a trend toward increased hippocampal neuron survival relative to vehicle-treated PS19 mice. Thus, despite evidence of dose-limiting peripheral side effects, the observed positive brain outcomes in dictyostatin-treated aged PS19 mice reinforces the concept that MT-stabilizing compounds have significant potential for the treatment of tauopathies.

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 45 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United States 1 2%
Unknown 44 98%

Demographic breakdown

Readers by professional status Count As %
Researcher 6 13%
Student > Bachelor 6 13%
Student > Ph. D. Student 5 11%
Student > Master 4 9%
Other 3 7%
Other 8 18%
Unknown 13 29%
Readers by discipline Count As %
Neuroscience 7 16%
Chemistry 7 16%
Pharmacology, Toxicology and Pharmaceutical Science 3 7%
Medicine and Dentistry 3 7%
Engineering 2 4%
Other 6 13%
Unknown 17 38%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 10. 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 07 October 2016.
All research outputs
#2,953,526
of 22,890,496 outputs
Outputs from Acta Neuropathologica Communications
#592
of 1,385 outputs
Outputs of similar age
#52,471
of 322,600 outputs
Outputs of similar age from Acta Neuropathologica Communications
#10
of 27 outputs
Altmetric has tracked 22,890,496 research outputs across all sources so far. Compared to these this one has done well and is in the 86th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 1,385 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 12.8. This one has gotten more attention than average, scoring higher than 54% 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 322,600 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 27 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 55% of its contemporaries.