Using a 22-year-old asthma drug, a Temple University research team was able to reverse signs of Alzheimer's brain damage and improve thinking ability in mice.
The team, led by Domenico Praticò, director of the Alzheimer's Center at Temple, gave zileuton to mice engineered to develop one of the hallmark proteins found in the brains of people with Alzheimer's disease. After 16 weeks on the drug, also called Zyflo, the mice were found to have 50 percent fewer tau tangles than mice that had not received the drug. The synapses, or connections between the brain cells, of the treated mice looked normal, while untreated mice had severe deterioration. The treated mice also performed better on a maze test of memory.
In recent years, most drug research to combat Alzheimer's disease has focused on amyloid, the other misformed protein found in people with the condition. So far, those attempts have been disappointing. Increasingly, researchers are exploring other pathways to treat the deadly form of dementia. Praticò said a couple other drugs aimed at tau are also currently being tested.
Mouse studies are notoriously frustrating. Many treatments that have looked promising in mice fail to work in humans.
Nonetheless, Praticò said that many previous mice studies attempted to prevent dementia. This one involved mice that were already showing symptoms of dementia. That's an important distinction because most people are not diagnosed with dementia until brain damage has already occurred.
"It's very, very exciting," Praticò said of the study results. "This could be the first time that we could do a treatment."
The study was published online Friday in the journal Molecular Neurobiology.
The mice in the Temple study were genetically engineered to develop tau tangles. They do not develop clumps of amyloid. People with Alzheimer's have both proteins. Praticò said that previous work showed that zileuton can also impact amyloid. However, he said, there is growing evidence that it is the tau tangles that are more closely correlated with cognitive problems in dementia.
The Temple researchers tried the drug because of their previous work on leukotrienes, inflammatory molecules that don't work properly in Alzheimer's disease or frontotemporal dementia.
Early on in dementia, leukotrienes are helpful, but they proliferate in later stages and cause damage. Praticò wanted to try blocking them.
The team used mice that were a year old, the equivalent of a 65- to 70-year-old human. After the treatment, which was equivalent in dose to what a human asthma patient would take, mice had 90 percent fewer leukotrienes than mice that got a placebo. The treated mice actually got better at the memory tests, performing similarly to a normal, aged mouse, Praticò said.
"It's really dramatic what we observed," he said. "For the first time, we are showing that we can do something after the disease is established."
He said one epidemiological study found that people with untreated asthma have higher-than-normal risk for dementia. The risk was lower in people who took a drug that blocked leukotrienes. That study did not compare the risk for treated asthma patients with people who did not have asthma.
So, should we all be taking zileuton to prevent dementia? Praticò doesn't think so. "I don't foresee this drug as a prevention," he said. However, he would not argue against taking it if you already likely have dementia pathology.
He is seeking funding for a clinical trial in people.
Carol Lippa, a Thomas Jefferson University neurologist who serves on the board of the Alzheimer's Association Delaware Valley Chapter, said she found the work by Praticò's team "very interesting." She said the new study builds on several years of positive findings from Temple about zileuton and related drugs and dementia.
"One of the really appealing aspects of this particular agent is that it's already FDA approved," she said. "All the big safety studies on it have already been done."
FDA guidelines on zileuton call for an assessment of liver function in people who take the drug. In addition to liver damage, it has been associated with sleep disorders and behavior changes. Some patients have allergic reactions. The most common side effects are nose and throat irritation, sinusitis, upper respiratory infection, throat pain, headache, muscle aches, nausea and diarrhea.