PHILADELPHIA — A study published this week in the Journal of Neuroscience shows that the compound epothilone D (EpoD) is effective in preventing further neurological damage and improving cognitive performance in a mouse model of Alzheimer's disease (AD). The results establish how the drug might be used in early-stage AD patients.
Investigators from the Perelman School of Medicine at the University of Pennsylvania, led by first author Bin Zhang, MD, PhD, senior research investigator, and senior author Kurt R. Brunden, PhD, Director of Drug Discovery at the Center for Neurodegenerative Disease Research (CNDR), administered EpoD to aged mice that had memory deficits and inclusions within their brains that resemble the tangles formed by misfolded tau protein, a hallmark of AD. In nerve cells, tau normally stabilizes structures called microtubules, the molecular railroad tracks upon which cellular cargo is transported. Tangles may compromise microtubule stability, with resulting damage to nerve cells. A drug that could increase microtubule stability might improve nerve-cell function in AD and other diseases where tangles form in the brain.
EpoD acts by the same microtubule-stabilizing mechanism as the FDA-approved cancer drug paclitaxel (Taxol™). These drugs prevent cancer cell proliferation by over-stabilizing specialized microtubules involved in the separation of chromosomes during the process of cell division. However, the Penn researchers previously demonstrated that EpoD, unlike paclitaxel, readily enters the brain and so may be useful for treating AD and related disorders.
After three months of receiving EpoD, additional tau clumps did not form in the brains of the aged AD mice, and nerve-cell function was increased compared to the AD mice that did not receive drug. What's more, the EpoD-treated mice showed improvements in learning and memory. Importantly, the doses of EpoD that resulted in these benefits were much lower than had previously been used in Phase II clinical testing of EpoD in cancer patients. The investigators observed no side-effects — including the suppression of the immune system and peripheral nerve damage -- in the transgenic mice that received EpoD.
These results suggest that low doses of EpoD might have therapeutic benefit in AD and related neurodegenerative diseases, such as frontotemporal lobar degeneration or progressive supranuclear palsy, where tangles are the primary brain pathology.
Co-authors Virginia M.-Y. Lee, PhD, CNDR director, and John Trojanowski, MD, PhD, director of the Institute on Aging at Penn and CNDR co-director, introduced the concept of using microtubule-stabilizing drugs over 15 years ago to counteract tangles of tau and compensate for the loss of normal tau function.
The Penn CNDR researchers, in collaboration with co-authors Amos B. Smith, III, PhD, the Rhodes Thompson Professor of Chemistry, and Carlo Ballatore, PhD, from the Penn Department of Chemistry, previously identified EpoD as a lead microtubule-stabilizing agent for evaluation in AD mouse models after characterizing several members of the epothilone family of compounds. Unlike many microtubule-stabilizing compounds, EpoD readily enters the brain, where it appears to persist for a much longer time than in the blood. This feature may explain why low doses were both effective and safe in the mouse model of AD.
The work significantly extends an earlier study published in the Journal of Neuroscience in October 2010.
The research was funded by the National Institute on Aging and the Marian S. Ware Alzheimer Program.
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