1. Academic Validation
  2. Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy

Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy

  • J Neurosci. 2010 Oct 13;30(41):13861-6. doi: 10.1523/JNEUROSCI.3059-10.2010.
Kurt R Brunden 1 Bin Zhang Jenna Carroll Yuemang Yao Justin S Potuzak Anne-Marie L Hogan Michiyo Iba Michael J James Sharon X Xie Carlo Ballatore Amos B Smith 3rd Virginia M-Y Lee John Q Trojanowski
Affiliations

Affiliation

  • 1 Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. kbrunden@upenn.edu
Abstract

Neurons in the brains of those with Alzheimer's disease (AD) and many frontotemporal dementias (FTDs) contain neurofibrillary tangles comprised of hyperphosphorylated Tau Protein. Tau normally stabilizes microtubules (MTs), and tau misfolding could lead to a loss of this function with consequent MT destabilization and neuronal dysfunction. Accordingly, a possible therapeutic strategy for AD and related "tauopathies" is treatment with a MT-stabilizing anti-cancer drug such as paclitaxel. However, paclitaxel and related taxanes have poor blood-brain barrier permeability and thus are unsuitable for diseases of the brain. We demonstrate here that the MT-stabilizing agent, epothilone D (EpoD), is brain-penetrant and we subsequently evaluated whether EpoD can compensate for tau loss-of-function in PS19 tau transgenic mice that develop forebrain tau inclusions, axonal degeneration and MT deficits. Treatment of 3-month-old male PS19 mice with low doses of EpoD once weekly for a 3 month period significantly improved CNS MT density and axonal integrity without inducing notable side-effects. Moreover, EpoD treatment reduced cognitive deficits that were observed in the PS19 mice. These results suggest that certain brain-penetrant MT-stabilizing agents might provide a viable therapeutic strategy for the treatment of AD and FTDs.

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