Contact: PLOS Biology
In search for Alzheimer’s drug, a major STEP forward
Researchers at Yale School of Medicine have discovered a new drug
compound that may help reverse the cognitive deficits of
Alzheimer’s disease. Their findings are publishing on August 5 in
the open access journal PLOS Biology.
The compound, TC-2153, inhibits the negative effects of a protein
called STriatal-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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Citation: Xu J, Chatterjee M, Baguley TD, Brouillette J, Kurup P,
et al. (2014) Inhibitor of the Tyrosine Phosphatase STEP Reverses
Cognitive Deficits in a Mouse Model of Alzheimer’s Disease. PLoS
Biol 12(8): e1001923. doi:10.1371/journal.pbio.1001923