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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


Year of Publication:
Contact PI Name:
Kurt R. Brunden
Contact PI Affiliation:
Center for Neurodegenerative Disease Research, Institute on Aging and Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Bin Zhang, Jenna Carroll, John Q. Trojanowski, Yuemang Yao, Michiyo Iba, Justin S. Potuzak, Anne-Marie L. Hogan, Sharon X. Xie, Carlo Ballatore, Amos B. Smith III, Virginia M-Y. Lee
Primary Reference (PubMED ID):
Funding Source:
Paula C. Schmerler Fund for Alzheimer's Research
Barrist Neurodegenerative Disease Research Fund
Eleanor Margaret Kurtz Endowed Fund
Mary Rasmus Endowed Fund for Alzheimer's Research
National Institute on Aging (NIA)
Karen Cohen Segal and Christopher S. Segal Alzheimer Drug Discovery Initiative Fund
Study Goal and Principal Findings:

In healthy neurons, tau is enriched in axons and promotes microtubule (MT) stabilization. It has been postulated that the sequestration of tau into insoluble inclusions results in disruption of normal tau function, which could alter MT stability and fast axonal transport (FAT). An approach to compensate for tau loss-of-function would be to use molecules that stabilize MTs.  Recently the authors identified epothilone D (EpoD) as a preferred MT-stabilizing compound for the potential treatment of tauopathies. The authors tested this hypothesis in a preventative study in which EpoD was administered weekly for 3 months to young PS19 tau Tg mice that initially lacked significant tau pathology. EpoD largely prevented the axonal MT loss and dystrophy, as well as spatial learning deficits, which manifested as these mice developed forebrain tau pathology with age. In the current study the authors test the therapeutic hypothesis that EpoD is efficacious in a prophylactic study- that is in PS19 Tg mice with established tau pathology.  EpoD treatment resulted in significant improvements of MT density, axonal integrity, FAT, and cognitive performance, without the onset of side effects. Moreover, EpoD treatment reduced hippocampal neuron and axon loss. Thus, EpoD safely corrected axonal defects in an interventional mouse model of AD-like tauopathy, suggesting that this agent has potential for the treatment of human tauopathies.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Epothilone D
Therapeutic Target:
Tubulin (Microtubules)

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Model Type:
Strain/Genetic Background:

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Y Maze
Barnes Maze
Misfolded Tau
Insoluble Tau
Fast Axonal Transport (FAT)
Neuronal Death
Electron Microscopy
Dystrophic Axons
Microtubule Density
Hematological Analysis/Blood Cell Count
Body Weight
Organ Weight
Peripheral Nerve Sensory Function