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

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.

Figure 1.

Pharmacokinetic testing of EpoD. A, EpoD concentrations in plasma and brain were determined at multiple time points after a single intraperitoneal administration. B, Brain concentrations of EpoD after an intraperitoneal dose of 3 mg/kg. Error bars represent SD. Plasma and brain EpoD concentrations were significantly different (p < 0.01) at all times in A as determined by two-tailed t tests using GraphPad Prism software with n = 3 mice/time.

Figure 2.

Axonal dystrophy in ON from PS19 mice. A–C, Electron micrographs of cross-sectional areas from ON at points equidistant from the globe of the eye and retina of 6-month-old WT mice (A) and PS19 mice (B, C). D, Axonal dystrophy in ON from 3- and 6-month-old male and female PS19 mice, and non-Tg (WT) littermates. E, Male WT and PS19 mice treated with EpoD or vehicle from 3 to 6 months of age were assessed for the number of dystrophic axons. Error bars represent SEM. **p < 0.01, ***p < 0.001, as determined by two-tailed t tests with n = 5–9 mice/group for D and n = 7–8 mice/group for E.

Figure 3.

ON MT density and tau brain pathology in EpoD- and vehicle-treated mice. A, MT density in WT and PS19 mice treated with EpoD or vehicle from 3 to 6 months of age. B, Relative phospho-tau immunostaining in coronal slices of brain hemispheres. Error bars represent SEM. *p < 0.05, **p < 0.01, ***p < 0.001 as determined by one-way ANOVA using a post hoc Bonferroni's multiple-comparison test with n = 7–8 mice/group (A). p > 0.05 in B as determined by Kruskal–Wallis analysis with n = 7–8 mice/group.

Figure 4.

Barnes maze performance of WT and PS19 mice treated with EpoD or vehicle. A, B, Percentage of trials that were successfully completed (A) and the number of errors per trial (B). Error bars represent SEM. *p < 0.05, **p < 0.01 as determined by a repeated-measures statistical analysis with n = 10–12 mice/group.