Every 67 seconds someone in the U.S. develops Alzheimer's disease, a form of progressive dementia for which there is no cure. Now, in the race to produce an effective treatment — or better still, find a cure — researchers at Yale School of Medicine have discovered a new compound that may reverse the cognitive effects of Alzheimer's disease. “A single dose of the drug results in improved cognitive function in mice,” says Dr. Paul Lombroso, professor in the departments of neurobiology and psychiatry. The drug, TC-2153, targets a particular enzyme known as striatal-enriched protein tyrosine phosphatase (or STEP), which is key to regulating learning and memory — the mental functions impaired by Alzheimer’s.
"Decreasing STEP levels reversed the effects of Alzheimer's disease in mice," said Lombroso, lead author of the new study examining TC-2153. The decision to find a compound that might decrease STEP levels is based upon various studies which have shown how levels of STEP are higher than normal in several neurological disorders, including Alzheimer's disease and schizophrenia. High levels of STEP keep synapses in the brain from strengthening, a process required for people when they are trying to turn short-term memories into long-term memories.
Understanding this, Lombroso and his colleagues studied thousands of small molecules, hunting for any that would obstruct STEP activity in the brain. After they identified a number of STEP-inhibiting compounds, each was tested on brain cells to see how effective they were in stopping the effects of STEP. Next, the team examined the single most promising compound in a mouse model of Alzheimer's disease. “Animals treated with TC compound were indistinguishable from a control group in several cognitive tasks,” Lombroso said. In fact, several exercises gauging the animals' ability to remember previously seen objects showed how the compound could reverse the impact of STEP.
TC-2153 is the result of a five-year effort, explained Lombroso. Now, the team is testing this compound in other animals, including rats and non-human primates. "Successful results will bring us a step closer to testing a drug that improves cognition in humans," Lombroso said. As more than five million Americans are living with Alzheimer's, many sufferers, and their families, have their fingers crossed.
Source: Xu J, Chatterjee M, Baguley TD, et al. Inhibitor of the Tyrosine Phosphatase STEP Reverses Cognitive Deficits in a Mouse Model of Alzheimer's Disease. PLOS Biology. 2014.