Washington: A team of researchers have found a drug therapy that aims to block ENSA activity could be a more effective treatment than what is currently available, as well as being cheaper.
The study has been published in the 'Molecular Psychiatry Journal'. The hallmark of Alzheimer's disease in the brain is the accumulation of amyloid b peptide (Ab). For years, researchers have been trying to determine how and why this happens.
Takaomi Saido and his team at RIKEN CBS have developed a mouse model of the disease that showed both Ab accumulation and memory deficits similar to what is seen in humans. Using this model mouse, they have already discovered a series of events in the brain that lead to the formation of Ab plaques.
Key among them is reduced levels of the enzyme neprilysin, which itself is caused by reduced levels of the hormone somatostatin. Levels of both neprilysin and somatostatin go down as we age, which can explain why Alzheimer's disease usually strikes older people.
The new study focused on treating Alzheimer's disease in mice by figuring out how somatostatin controls neprilysin levels in the brain.
According to first author Naoto Watamura, "the first step in this process was actually the most difficult because we had to develop an in vitro system that could screen for neprilsyin regulators in conditioned medium generated by hippocampal neurons."
Once they accomplished this, they were able to identify ENSA as the regulator. Testing showed that ENSA reduced neprilysin activity and that it rose to abnormally high levels in the brains of mice that lacked somatostatin. This meant that somatostatin normally keeps ENSA in check, which in turn kept neprilsyin levels high, allowing Ab to be destroyed before it accumulated.
Next, the team focused on ENSA in living animals. Using CRISPR technology, they created ENSA knockout mice and then bred them with the Alzheimer's disease model mice. Ab accumulation in these new mice was much lower than in the original model mice, indicating that abnormally high levels of ENSA could be an as yet unidentified symptom or biomarker of Alzheimer's disease. This was confirmed when the researchers detected a high level of ENSA in the model mice and in the brains of people with Alzheimer's disease.
What exactly is ENSA doing in the brain? Tests showed that ENSA blocks a potassium channel in the hippocampus, a part of the brain needed for making and recalling memories.
"Because we got the same results from blocking the KATP channel as we did from the ENSA knockout mice, we reasoned that helping the channel stay open would combat the excess ENSA that we observed in Alzheimer's disease," said Watamura.
To test this theory, the researchers fed the model mice with diazoxide -- a drug that activates the KATP channel -- and tested their memory. They found that while the untreated Alzheimer's disease model mice exhibited their characteristically poor memory, the treated model mice performed just as well as normal mice. A look at the brains of the treated mice showed that they lacked the hallmark Ab plaques.
"Our findings point directly to a potential way of preventing and treating Alzheimer's disease. On top of that, compared with Ab-targeting immunotherapy, such as the drug aducanumab, which was recently approved by the FDA, synthetic agonists for the KATP channel are less expensive and would be more acceptable to ageing societies around the world," said Watamura.