New drug class treats neurodegeneration
neurodegenerative disorders such as Alzheimer's could herald a
breakthrough in drug treatment for a disease that affects up to 4
million adults in the United States, and 10 million worldwide.
In the preclinical efficacy trial, researchers tested a microtubule-stabilizing drug that helped correct the problems caused by clumped tau proteins in the nerve cells of mice.
Tau amyloids are misshapened, insoluble proteins that clump in the brain and elsewhere and cause a host of debilitating diseases. Since many neurodegenerative diseases contribute to this pathology, the focus of therapy has been on drugs that break up these aggregates.
The concept of using microtubule-stabilizing drugs was introduced over a decade ago. Whilst the majority of current research focused on drugs that disrupted the aggregated protein, the focus now is to find a drug that replaced the clumped tau in sick neurons.
In a sick neuron, tau is clumped into aggregates, so the microtubule cross-ties are missing 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.
"Our hope is that microtubule-stabilizing drugs could be used to treat Alzheimer's and other related diseases," said John Trojanowski, co-director of the centre for neurodegenerative disease research.
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 system of axons in nerve cells. Mutations in the tau gene cause neurons to lose their ability to send and carry signals.
"When these misfolded proteins aggregate and form sheets called fibrils that accumulate in different parts of the brain, that's when things go awry," said Trojanowski.
This occurs when the cell's dumping ground, 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.
Trojanowski commented that microtubule-binding drugs such as Paxceed are already approved for treating patients with cancer and a limited number of other diseases. Thus, it might be possible to move quickly to clinical trials of these types of compounds.
However, the research done by scientists from the University of Pennsylvania School of Medicine, would then need to develop microtubule-binding drugs that can cross the blood-brain barrier. This is where they can exert their beneficial effects on nerve cells inside the brain.
