DRUG REVERSES BRAIN DEFICITS OF ALZHEIMER'S IN MOUSE MODEL
Researchers at Yale
School of Medicine have discovered a new drug compound that reverses the brain
deficits of Alzheimer's disease in an animal model.
Their
findings are published in the Aug. 5 issue of the journal PLoS
Biology.
The
compound, TC-2153, inhibits the negative effects of a protein called
STtriatal-Enriched tyrosine Phosphatase (STEP), which is key to regulating
learning and memory. These cognitive functions are impaired in Alzheimer's.
"Decreasing
STEP levels reversed the effects of Alzheimer's disease in mice," said
lead author Paul Lombroso, M.D., professor in the Yale Child Study Center and
in the Departments of Neurobiology and Psychiatry at Yale School of Medicine.
Lombroso
and co-authors studied thousands of small molecules, searching for those that
would inhibit STEP activity. Once identified, those STEP-inhibiting compounds
were tested in brain cells to examine how effectively they could halt the
effects of STEP. They examined the most promising compound in a mouse model of
Alzheimer's disease, and found a reversal of deficits in several cognitive
exercises that gauged the animals' ability to remember previously seen objects.
High
levels of STEP proteins keep synapses in the brain from strengthening. Synaptic
strengthening is a process that is required for people to turn short-term
memories into long-term memories. When STEP is elevated in the brain, it
depletes receptors from synaptic sites, and inactivates other proteins that are
necessary for proper cognitive function. This disruption can result in
Alzheimer's disease or a number of neuropsychiatric and neurodegenerative
disorders, all marked by cognitive deficits.
"The
small molecule inhibitor is the result of a five-year collaborative effort to
search for STEP inhibitors," said Lombroso. "A single dose of the
drug results in improved cognitive function in mice. Animals treated with TC
compound were indistinguishable from a control group in several cognitive
tasks."
The
team is currently testing the TC compound in other animals with cognitive
defects, including rats and non-human primates. "These studies will
determine whether the compound can improve cognitive deficits in other animal
models," said Lombroso. "Successful results will bring us a step
closer to testing a drug that improves cognition in humans."
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