7 January 2005. Taxols, drugs that are commonly used to treat cancer, may offer some therapeutic benefit for patients suffering from Alzheimer disease (AD) and other neurodegenerative diseases, such as frontotemporal dementia, in which aggregates of the microtubule-binding protein tau are found. That’s the tantalizing conclusion of a paper, by John Trojanowski and colleagues, which appeared in the Jan 4 PNAS.
Taxols, such as paclitaxel, bind to and stabilize microtubules. Recall that these long protein chains provide extensive rail-like networks that are indispensable for intracellular transportation of all kinds of cargo. In neurons, the microtubules are essential for the movement of proteins up and down axons, a process that is thought to be expedited by microtubule-binding factors such as tau (although, see ARF related news story suggesting that removal of tau from microtubules speeds up transport).
But in AD, and some other neurodegenerative diseases, tau becomes sequestered in neurofibrillary tangles, preventing its access to microtubules and scuppering axonal transport (see ARF related news story). Could other molecules compensate for this loss? What about taxols? By stabilizing microtubules, might they give a boost to axonal transport? In vitro evidence suggests that this might be the case (see Michaelis et al., 2004). Trojanowski and colleagues at University of Pennsylvania School of Medicine, Philadelphia, set out to discover if the same would hold true in vivo.
When first author Bin Zhang and colleagues administered paclitaxel to transgenic mice that overexpress human tau—which then accumulates in intracellular aggregates—the researchers found that the taxol did indeed increase fast axonal transport. More protein was transported farther along axons and less protein cargo was found to be immobile in transgenics that were given the taxol as compared to animals given placebo. The authors found these statistically meaningful differences in the lumbar ventral root axons that are involved in neuromuscular signaling and which easily take up the drug.
The improvement in fast axonal transport is likely due to stabilization of microtubules because the authors found about 25 percent fewer tubules in placebo-treated animals. The taxol also seemed to prevent neurodegeneration, because when the authors analyzed ventral root sections, they found that axons from transgenic animals appeared normal if they had been given paclitaxel, but axons from animals treated with placebo appeared irregular and showed signs of degeneration.
Overtly, the paclitaxel treatment also led to significant improvement in motor function. Transgenic mice 9-12 months old typically have about a 30 percent loss of motor activity (assessed in this case by their ability to pull themselves up when suspended by the tail), but those animals given the highest does of paclitaxel had only about a seven percent loss—comparable to age-matched, non-transgenic controls. The ability of paclitaxel to restore motor function to near normal begs the question: Could it have a similar effect on cognitive function? The answer to that may come from studies on a different disease model.—Tom Fagan.
Zhang B, Maiti A, Shively S, Lakhani F, McDonald-Jones G, Bruce J, Lee EB, Xie SX, Joyce S, Li C, Toleikis PM, Lee VM-Y, Trojanowski JQ. Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model. PNAS Jan 4 2004;102:227-231. Abstract