Last week, a research team led by Yale School of Medicine professor Paul Lombroso published findings that linked schizophrenia and Alzheimer’s disease.
Lombroso, along with Kristen Brennand of the Icahn School of Medicine at Mount Sinai, found that both conditions are caused by overproduction of a protein known as striatal-enriched protein tyrosine phosphatase, or STEP, which removes receptors from the synaptic sites of neurons.
According to Lombroso’s previous work, elevated levels of STEP lead to significant removal of these receptors. In their absence, synaptic signals can no longer pass between affected neurons, and cognitive function declines.
Although Lombroso said that this phenomenon was relevant to a number of cognitive disorders, including schizophrenia, Alzheimer’s disease and fragile X syndrome, STEP levels are also somewhat elevated in older people.
“The central theme is that if STEP is overactive, it disrupts synaptic function and may contribute to the cognitive deficits that occur in a host of different [central nervous system] disorders,” Lombroso said.
In its most recent study, Lombroso’s team used two methods in an attempt to lower STEP activity in the brain and possibly restore lost cognitive function, Lombroso said. The researchers’ first approach involved crossing schizophrenic mice with “STEP knockout mice”— which do not have any of the STEP protein. The progeny of these crosses then had the mutation necessary for schizophrenia but lacked the STEP protein, Lombroso said.
As a result, these mice did not exhibit any symptoms of schizophrenia and were indistinguishable from wild-type mice.
According to the study, the team then used an inhibitor, TC 2153, to suppress STEP activity in mice that exhibited schizophrenia. They subsequently found that three hours after a single injection of TC 2153, previously affected receptors returned to synaptic membranes and the cognitive condition of the mice was again identical to that of wild-type mice.
The team also used differentiated pluripotent stem cells in order to replicate the brain cells of human subjects with schizophrenia. They found, as expected, that the pluripotent cells contained a high amount of STEP protein and that many of their synaptic glutamate receptors were inhibited.
As in the case of the mice, the introduction of the TC compound “reversed the biochemical abnormalities as well as corrected the collective physiologies” of the human cell replicates, Lombroso said.
Lombroso added that the impact of his team’s work was not limited to schizophrenia. He noted that a drug that targets the STEP protein may also prove effective in treating Alzheimer’s disease, fragile X syndrome, Parkinson’s disease and other cognitive disorders associated with overactivity of the STEP protein. In each of these conditions, he said, a single protein that regulates the formation of long-term memories from short-term memories has been disrupted.
According to Lombroso, although the root causes of these conditions are similar, a patient’s development of a specific cognitive disorder depends on the region of the brain in which STEP is overactive.
He added that, for example, in Parkinson’s disease, the overexpression of STEP occurs in the brain region that regulates motor movement, but in Alzheimer’s disease and schizophrenia, the elevation of STEP activity takes place in the cortex, suggesting that a particular neurological function is affected.
“The structure [of the TC compound used to suppress STEP] is such that [pharmaceutical companies] think it might interact with a number of other proteins because it has a ring of five sulfurs,” Lombroso said. “It’s a wonderful drug for the laboratory and for us to use to inhibit STEP’s activity, and it has proven that inhibition of STEP is effective in reversing cognitive deficits and biochemical deficits, but a new family of drug is needed.”
Emily Kemp, a researcher at the Yale Alzheimers Disease Research Unit, said that although the results of the study were exciting, they should be interpreted with a healthy level of skepticism.
She added that decreasing STEP levels would only be useful until the structure of neurons deteriorates and that pharmocological manipulation of STEP may show more benefit for schizophrenia than for Alzheimer’s and other dementias.
Lombroso said he remains optimistic about the study findings, since an approach centered on STEP targeting differs from approaches taken in the development of earlier cognitive disorder treatments. Most of the drugs developed for schizophrenia in previous decades have been of the same class, and there are currently no new medications in the field, Lombroso said.
“In Alzheimer’s, for that matter, there’s been very little advancement in the treatment of the cognitive deficits, and the drugs that exist are only effective for a few months, so new drugs are needed, and this is one example,” Lombroso said.
Schizophrenia has a twelve-month prevalence of 1.1 percent within the US population, according to the National Institutes of Health.