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Potent anticancer drug increases function of axons in mouse model of neurodegeneration

21.12.2004


Paxceed shows therapeutic promise for diseases involving brain amyloids

In a preclinical efficacy trial, the cancer drug paclitaxel (Paxceed)–which exerts its effects by binding to and stabilizing microtubules inside cells–reduced the adverse effects of Alzheimer’s disease (AD)-like pathology in a mouse model. Researchers from the University of Pennsylvania School of Medicine showed that the microtubule-stabilizing drug Paxceed helps correct the problems caused by clumped tau proteins in the nerve cells of mice. "Our hope is that microtubule-stabilizing drugs could be used to treat Alzheimer’s and other related diseases," says John Q. Trojanowski, MD, PhD, Director of the Institute on Aging and Co-director of the Center for Neurodegenerative Disease Research and the Marian S. Ware Alzheimer Program at Penn. This research appears in the December 20 early online edition of the Proceedings of the National Academy of Sciences.

Tau amyloids are misshapened, insoluble proteins that clump in the brain and elsewhere and cause a host of debilitating diseases. Since many neurodegenerative diseases share or contribute to this pathology, the focus of therapy has been on drugs that break up these aggregates. Virginia M.-Y. Lee, PhD, Director of the Center for Neurodegenerative Disease Research, and Trojanowski introduced the concept of using microtubule-stabilizing drugs over a decade ago, and this is the first study to confirm their potential as a new class of drug for neurodegenerative disorders. "Now everyone is focused on drugs that disrupt the aggregated protein," says Trojanowski. "We’re working on that too, but we also wanted to find a drug that replaces the clumped tau in sick neurons."



Microtubule-binding drugs derived from plants (taxol) and other biological organisms such as sponges (discodermolides) have been used as anti-cancer drugs because they prevent cells from dividing. They do this by keeping microtubules stabilized, which blocks cell division and causes cell death. Microtubules are protein structures found within cells.

Since neurons do not divide, Paxceed does not affect them in the same way as normally dividing cells and tumor cells. Instead, microtubule-binding drugs have other effects in nerve cells similar to the function of the protein tau.

Tau binds microtubules, the highway system of axons in nerve cells. Mutations in the tau gene cause neurons to lose their ability to send and carry signals over time. "These are proteins that we all have in our brains and, as long as they stay soluble and properly folded, there’s no disease," says Trojanowski. "When these misfolded proteins aggregate and form sheets called fibrils that accumulate in different parts of the brain, that’s when things go awry." This happens when the cell’s garbage disposal–the proteosome–isn’t working properly or is overwhelmed, causing such affects as cell death, oxidative stress, and in this case impaired axonal transport, which is linked to many neurodegenerative diseases. Impaired axonal transport of proteins and other cargoes needed to maintain synapses can cause nerve cell loss with subsequent dementia, parkinsonism or weakened motor skills in peripheral muscles, and later muscle atrophy.

The protein tau, like Paxceed (or other natural products such as taxanes and discodermolides), is required to stabilize the microtubule. "Think of tau as the cross-tie of the microtubule train track," says Trojanowski. "The tracks will handle the traffic as long as they are parallel and there are substrates for transport. If the cross-ties are missing, the tracks will wobble and the train will run off the tracks."

In a sick neuron, tau is clumped into aggregates, so the microtubule cross-ties are missing, the tracks break, and transmission of nerve signals fails. In the hopes of restoring the microtubule tracks to their original supportive structure, the researchers gave mice Paxceed to replace the now unavailable tau. The team, led by Bin Zhang, PhD, a Senior Research Investigator in Trojanowski’s and Lee’s laboratory, gave the tau transgenic mice weekly injections of Paxceed at a high and low dose for 12 weeks. At both doses, more protein traveled down the spinal axon and the density of microtubules was greater in the Paxceed-treated mice. The drugs also reduced motor impairment in the tau transgenic mice.

Because microtubule-binding drugs such as Paxceed are approved for treating patients with cancer and a limited number of other diseases, it might be possible to move quickly to clinical trials of these types of compounds, say the researchers. However, it will be necessary to find microtubule-binding drugs that can cross the blood-brain barrier, where they can exert their beneficial effects on nerve cells inside the brain.

Penn coauthors are: Sharon Shively, Jennifer Bruce, Edward B. Lee, Sharon X. Xie, Sonali Joyce, Chi Li, along with Angiotech Pharmaceticals, Inc. (Vancouver, BC) colleagues Arpita Maiti, Fara Lakhani, Gaye McDonald-Jones, and Philip M. Toleikis. The research was funded by the National Institutes of Health, the Oxford Foundation, the Marian S. Ware Alzheimer Program, and Angiotech. Drs. Trojanowski and Lee hold no financial interests in Angiotech.

Karen Kreeger | EurekAlert!
Further information:
http://www.uphs.upenn.edu/news

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