The Microtubule-Stabilizing Agent, Epothilone D, Reduces Axonal Dysfunction, Neurotoxicity, Cognitive Deficits, and Alzheimer-Like Pathology in an Interventional Study with Aged Tau Transgenic Mice

Authors:
  • JCJenna Carroll
    Jenna Carroll
  • JTJohn Q. Trojanowski
    John Q. Trojanowski
  • YYYuemang Yao
    Yuemang Yao
  • MIMichiyo Iba
    Michiyo Iba
  • JPJustin S. Potuzak
    Justin S. Potuzak
  • AHAnne-Marie L. Hogan
    Anne-Marie L. Hogan
  • SXSharon X. Xie
    Sharon X. Xie
  • ASAmos B. Smith
    Amos B. Smith
  • VLVirginia M.-Y. Lee
    Virginia M.-Y. Lee
Open Access
Publisher website
Google Scholar
Abstract
Neurodegenerative tauopathies, such as Alzheimer's disease (AD), are characterized by insoluble deposits of hyperphosphorylated tau protein within brain neurons. Increased phosphorylation and decreased solubility has been proposed to diminish normal tau stabilization of microtubules (MTs), thereby leading to neuronal dysfunction. Earlier studies have provided evidence that small molecule MT-stabilizing drugs that are used in the treatment of cancer may have utility in the treatment of tauopathies. However, it has not been established whether treatment with a small molecule MT-stabilizing compound will provide benefit in a transgenic model with pre-existing tau pathology, as would be seen in human patients with clinical symptoms. Accordingly, we describe here an interventional study of the brain-penetrant MT-stabilizing agent, epothilone D (EpoD), in aged PS19 mice with existing tau pathology and related behavioral deficits. EpoD treatment reduced axonal dystrophy and increased axonal MT density in the aged PS19 mice, which led to improved fast axonal transport and cognitive performance. Moreover, the EpoD-treated PS19 mice had less forebrain tau pathology and increased hippocampal neuronal integrity, with no dose-limiting side effects. These data reveal that brain-penetrant MT-stabilizing drugs hold promise for the treatment of AD and related tauopathies, and that EpoD could be a candidate for clinical testing.

This publication has 64 references indexed in Scilit: