In this month’s issue of PLoS Biology, in an article entitled, “Inhibitor of the Tyrosine Phosphatase STEP Reverses Cognitive Deficits in a Mouse Model of Alzheimer’s Disease,” researchers revealed that TC-2153 inhibits the negative effects of STEP (Striatal-Enriched protein tyrosine Phosphatase), a neuron-specific phosphatase that regulates several other proteins, and a key player in the regulation of learning and memory.
Different studies have reported an overactivation of STEP in several neuropsychiatric and neurodegenerative disorders, leading to disrupted synaptic strengthening, a process required to turn short-term memories into long-term memories. Thus, the enhanced levels of STEP in the brain are likely to contribute to the cognitive deficits observed in Alzheimer’s.
The investigators engineered mice that develop AD and are deficient in STEP, observing that these animals can restore the levels of glutamate receptors on synaptosomal membranes and improve cognitive function, suggesting STEP as a novel therapeutic target for AD.
A large-scale scan was then preformed to identify and characterize small-molecule STEP inhibitors, finding TC-2153 (benzopentathiepin 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-aminehydrochloride) as an inhibitor of STEP. This small-molecule compound belongs to a novel class of protein tyrosine phosphatase (PTP) inhibitors and forms reversible covalent bonds with the catalytic cysteine in STEP. Administration of TC-2153 resulted in improved cognitive function in several perceptive tasks in 6- and 12 months old transgenic mice. Importantly, TC-2153 proved be specific towards STEP compared to several other tyrosine phosphatases and was not toxic to neurons cultures in vitro.
“The small molecule inhibitor is the result of a five-year collaborative effort to search for STEP inhibitors,” 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, as quoted in a recent YSM press release. “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 research team is currently testing the TC-2153 compound in other animals with cognitive defects, including rats and non-human primates, to determine if it can improve cognitive deficits in models other than mice.
If these studies prove to be successful, it will be an important step towards the development of a drug with the potential to improve cognition in humans.
This study was funded by the National Institute of Health, the American Health Assistance Foundation, and the Alzheimer’s Drug Discovery Foundation.
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