RT Journal Article
SR Electronic
T1 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
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3601
OP 3611
DO 10.1523/JNEUROSCI.4922-11.2012
VO 32
IS 11
A1 Zhang, Bin
A1 Carroll, Jenna
A1 Trojanowski, John Q.
A1 Yao, Yuemang
A1 Iba, Michiyo
A1 Potuzak, Justin S.
A1 Hogan, Anne-Marie L.
A1 Xie, Sharon X.
A1 Ballatore, Carlo
A1 Smith, Amos B.
A1 Lee, Virginia M.-Y.
A1 Brunden, Kurt R.
YR 2012
UL http://www.jneurosci.org/content/32/11/3601.abstract
AB 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.