Neurons within the brains of those with AD (Alzheimer's disease) and related neurodegenerative disorders, collectively termed ‘tauopathies’, contain fibrillar inclusions composed of hyperphosphorylated tau protein. Tau is normally enriched in axons, where it binds and stabilizes MTs (microtubules). Tau hyperphosphorylation and aggregation probably result in reduced MT binding that could affect axonal transport and neuronal function. A possible therapeutic strategy to overcome a loss of tau function in tauopathies is administration of MT-stabilizing agents, such as those used in the treatment of cancer. However, these drugs elicit severe side effects, and most existing MT-stabilizing compounds have poor BBB (blood–brain barrier) permeability, which renders them unsuitable for tauopathy treatment. We identified EpoD (epothilone D) as a brain-penetrant MT-stabilizing agent with preferred pharmacokinetic and pharmacodynamic properties. EpoD was evaluated for its ability to compensate for tau loss-of-function in an established Tg (transgenic) mouse model, using both preventative and interventional dosing paradigms. EpoD at doses much lower than previously used in human cancer patients caused improved axonal MT density and decreased axonal dystrophy in the tau Tg mice, leading to an alleviation of cognitive deficits. Moreover, EpoD reduced the extent of tau pathology in aged tau Tg mice. Importantly, no adverse side effects were observed in the EpoD-treated mice. These results suggest that EpoD might be a viable drug candidate for the treatment of AD and related tauopathies.
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August 2012
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Conference Article|
July 20 2012
Brain-penetrant microtubule-stabilizing compounds as potential therapeutic agents for tauopathies
Kurt R. Brunden;
Kurt R. Brunden
1
*Center for Neurodegenerative Disease Research, Institute on Aging and Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
1To whom correspondence should be addressed (emailkbrunden@upenn.edu).
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Carlo Ballatore;
Carlo Ballatore
*Center for Neurodegenerative Disease Research, Institute on Aging and Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
†Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
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Virginia M.-Y. Lee;
Virginia M.-Y. Lee
*Center for Neurodegenerative Disease Research, Institute on Aging and Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
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Amos B. Smith, III;
Amos B. Smith, III
†Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
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John Q. Trojanowski
John Q. Trojanowski
*Center for Neurodegenerative Disease Research, Institute on Aging and Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
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Publisher: Portland Press Ltd
Received:
January 16 2012
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem Soc Trans (2012) 40 (4): 661–666.
Article history
Received:
January 16 2012
Citation
Kurt R. Brunden, Carlo Ballatore, Virginia M.-Y. Lee, Amos B. Smith, John Q. Trojanowski; Brain-penetrant microtubule-stabilizing compounds as potential therapeutic agents for tauopathies. Biochem Soc Trans 1 August 2012; 40 (4): 661–666. doi: https://doi.org/10.1042/BST20120010
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