Tangled Up in Tau
Knowing that problems with tau play a role in Alzheimer’s disease as well as in so many other types of dementia puts a premium on finding ways to avoid its destruction. During the past decade, much research has focused on how to inhibit kinases, the enzymes that cause phosphates to accumulate around tau and lead it to break away from microtubules. But kinases have many other functions, and inhibitors designed to reduce their activity have failed in clinical trials, says Virginia Lee. Another idea is to eliminate tangles of tau by turning on cellular machinery that normally gets rid of protein waste. “But if you activate this garbage disposal, you might do damage to the cell,” Lee says. “We need to find something more specific.”
For several years, Lee and Trojanowski have experimented with using cancer drugs to stabilize MTs that are weakened when tau breaks away. As cancer treatments, such drugs work by preventing the normal disassembly of MTs that must occur so cells can divide—and because they can’t replicate themselves, treated cancer cells (and many others) die. But neurons, which don’t divide, are immune to the toxicity of chemotherapy and might benefit from having their MTs shored up.
One problem with that approach is that most chemotherapy drugs can’t get past the blood-brain barrier to reach neurons in the brain. But Lee and Trojanowski eventually found one that did, and in 2010 they used that agent, epothilone D, to treat mice they had engineered to develop memory deficits from tau tangles. First, the scientists gave the drug to very young mice that were just starting to develop cognitive impairments. The treatment increased the number of MTs and improved cognition. In a later study, involving older mice whose symptoms had become more severe, the drug not only succeeded at restoring MTs and cognition but also brought a “stunning reduction in tangle pathology, which we didn’t expect,” says Trojanowski.
Epothilone D and another drug designed to stabilize MTs are now being tested in human clinical trials. If the drugs prove effective at clearing tau tangles, patients would have to take them long term—normally a problem with toxic chemotherapy agents. But in mice, very small amounts of epothilone D—just 1% of what would be given to attack cancer—obliterated tau tangles. “Giving such a small dose once a week to people would be way below the threshold at which you would see toxicity and side effects,” Trojanowski says.
Halting tau production in the brain might be another way to reverse the ravages of tauopathies. Hyman’s team and other research groups recently showed that when they turned off the tau gene in mice for six months, nearly all of their tau tangles disappeared—a result that challenged long-held assumptions that tau lesions were irreversible. “But the mouse studies just establish biological plausibility,” says Hyman. “We don’t have the tools to turn off tau in people.”
One potentially better approach that would slow the aggregation involves a drug called methylene blue. Already approved by the FDA for conditions such as pediatric malaria and urinary tract infections, a modified form of the drug is being tested for FTD and mild to moderate Alzheimer’s disease. And Eckhard Mandelkow’s wife, Eva-Maria Mandelkow, also at the German Center for Neurodegenerative Diseases, has shown that the drug—which, like epothilone D, penetrates the blood-brain barrier—can prevent the damaging effects of tau in mice.