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.