The Alzheimer's Cure That Worked on Mice

Lab mouse
In mouse models, the compound TC-2153 reversed the effects of Alzheimer's disease. Alessia Pierdomenico/REUTERS

Researchers at Yale School of Medicine announced the discovery of a drug compound that reverses the effects of Alzheimer's disease in mice.

The study published Tuesday in the open access journal PLOS Biology identifies the compound as TC-2153, which prevents the protein STEP (STriatal-Enriched tyrosine Phosphatase) from destroying the brain's ability to learn and retain new things. STEP was discovered twenty-five years ago by Yale School of Medicine professor and leading author of the study, Dr. Paul Lombroso.

Since that discovery, a number of studies have shown that patients with Alzheimer's, Parkinson's, schizophrenia, and fragile x syndrome—the most common known cause of inherited intellectual disability—all have elevated levels of STEP.

The protein STEP attacks neurotransmitters in the brain called glutamate receptors, which allow us to turn short-term memories into long-term memories. This process is critical to learning anything from names, faces, facts, and stories to motor skills, like riding a bike, to spatial information, like the layout of our home.

Several years ago, researchers found that when they genetically lowered STEP levels in mice that were given Alzheimer's disease genes, the cognitive performance of the sick mice was indistinguishable from that of healthy mice. "This was very exciting," Lombroso says, "because it suggested that . . . inhibiting STEP's activity [may] be sufficient" to reverse the cognitive deficits of people with Alzheimer's.

It's not viable, however to genetically lower STEP levels in human Alzheimer's patients. So instead, for the past five years, Lombroso and his colleagues have been using STEP as a "target for drug discovery." They've been sifting through and studying thousands of small molecules, searching for those that would inhibit STEP activity. They finally found one.

As the paper published Tuesday reports, a single dose of the compound TC-2153 was enough to reverse the effects of Alzheimer's disease in mice. Several cognitive exercises were used in the study to gauge the animals' ability to learn and remember various motor skills, spatial information, warning signals, and previously seen objects.

One test Lombroso described to Newsweek was the Morris Water Maze. The setup is a basin of water. There is a platform located in one section of the basin, invisible beneath the water's surface. On the sides of the basin are different symbols (e.g. circle, cross, triangle), which become spatial references that help a mouse placed in the water again and again to eventually learn the location of the platform. Lombroso explains that after a few days of trainings, a healthy mouse knows exactly where the platform is and will swim directly to it. Mice with Alzheimer's, however, cannot learn, because their excess STEP protein has destroyed the neurotransmitters responsible for turning short-term memories into long-term memories. On the fifth day of training, they're still swimming around in the water just as lost as they were on the first day.

Amazingly, this study found that, after a dose of the STEP inhibitor, the Alzheimer's mice were able to learn. In the Morris Water Maze and every other cognitive test, these mice performed just as well as healthy mice. In other words, administration of the compound effectively reversed the cognitive deficits brought on by Alzheimer's.

Yet much more testing is still required before we can start manufacturing drugs with the TC-2153 compound. Adding a "cautionary note," Lombroso says, "Many drugs have been successful in the mouse and failed in the humans." His team is currently trying to replicate the results with other animals, including rats and nonhuman primates.

Meanwhile, the search is still on for more STEP inhibitors. The pharmaceutical company GlaxoSmithKline is currently screening a million compounds, looking for additional drug candidates. "I am optimistic that in the next couple of years we will have identified a whole slew of STEP inhibitors," Lombroso says, explaining that a whole slew is necessary, because one never knows which candidates will pass test after test and eventually make it onto drugstore shelves.

Uncommon Knowledge

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Newsweek is committed to challenging conventional wisdom and finding connections in the search for common ground.

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Louise Stewart is an undergraduate at Stanford University, majoring in English with a creative writing emphasis and joining Newsweek for ... Read more

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