Evaluation of the brain-penetrant microtubule-stabilizing agent, dictyostatin, in the PS19 tau transgenic mouse model of tauopathy.

Vishruti Makani,Kevin Lou,Bin Zhang,Ian Paterson,Amos B Smith,Yuemang Yao,Carlo Ballatore,Virginia M Y Lee,Kurt R Brunden,Heeoon Han,John Q Trojanowski,Pierrik Lassalas

doi:10.1186/s40478-016-0378-4

Abstract

Neurodegenerative disorders referred to as tauopathies, which includes Alzheimer’s disease (AD), are characterized by insoluble deposits of the tau protein within neuron cell bodies and dendritic processes in the brain. Tau is normally associated with microtubules (MTs) in axons, where it provides MT stabilization and may modulate axonal transport. However, tau becomes hyperphosphorylated and dissociates from MTs in tauopathies, with evidence of reduced MT stability and defective axonal transport. This has led to the hypothesis that MT-stabilizing drugs may have potential for the treatment of tauopathies. Prior studies demonstrated that the brain-penetrant MT-stabilizing drug, epothilone D, had salutary effects in transgenic (Tg) mouse models of tauopathy, improving MT density and axonal transport, while reducing axonal dystrophy. Moreover, epothilone D enhanced cognitive performance and decreased hippocampal neuron loss, with evidence of reduced tau pathology. To date, epothilone D has been the only non-peptide small molecule MT-stabilizing agent to be evaluated in Tg tau mice. Herein, we demonstrate the efficacy of another small molecule brain-penetrant MT-stabilizing agent, dictyostatin, in the PS19 tau Tg mouse model. Although dictyostatin was poorly tolerated at once-weekly doses of 1 mg/kg or 0.3 mg/kg, likely due to gastrointestinal (GI) complications, a dictyostatin dose of 0.1 mg/kg was better tolerated, such that the majority of 6-month old PS19 mice, which harbor a moderate level of brain tau pathology, completed a 3-month dosing study without evidence of significant body weight loss. Importantly, as previously observed with epothilone D, the dictyostatin-treated PS19 mice displayed improved MT density and reduced axonal dystrophy, with a reduction of tau pathology and a trend toward increased hippocampal neuron survival relative to vehicle-treated PS19 mice. Thus, despite evidence of dose-limiting peripheral side effects, the observed positive brain outcomes in dictyostatin-treated aged PS19 mice reinforces the concept that MT-stabilizing compounds have significant potential for the treatment of tauopathies.

Highlights

Neurodegenerative tauopathies, a group of diseases including Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Pick’s disease, are characterized by the presence of inclusions within neurons comprised of the microtubule (MT)binding protein, tau [4, 25, 33]
Like epothilone D, provided benefit to the central nervous system (CNS) of PS19 mice, improving MT density and decreasing axonal abnormalities while reducing tau pathology, with a trend towards increased hippocampal neuron survival
Dictyostatin improved brain MT density and reduced both axonal dystrophy and tau pathology in PS19 tau Tg mice, with a trend toward lessened hippocampal neuron loss We demonstrated previously that aged PS19 mice have a modest deficit in MT density, as determined through a comparison of MT counts in cross-sectional electron microscopic images of optic nerve (ON) sections from non-Tg littermates and PS19 tau Tg mice [15, 46], which harbor tau pathology in retinal ganglia cells [15]

Summary

Introduction

Neurodegenerative tauopathies, a group of diseases including Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Pick’s disease, are characterized by the presence of inclusions within neurons comprised of the microtubule (MT)binding protein, tau [4, 25, 33]. We [15, 46] and others [5] have demonstrated that the brain-penetrant MT-stabilizing agent, epothilone D (Fig. 1), significantly improves behavioral and AD-like brain pathological outcomes in Tg mouse tauopathy models This includes increased MT density, reduced axonal dystrophy, and improved axonal transport with a salvaging of hippocampal neurons and an apparent reduction of tau pathology. Epothilone D is the only non-peptide small molecule MT-stabilizing compound that has been shown to reduce the consequences of tau inclusion formation in Tg mouse models of tauopathy, the octapeptide NAP ( called davunetide) has been shown to improve outcomes in tau Tg mice through mechanisms [34] that include MT stabilization [20, 35]

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Conclusion