2023-08-20 06:00:48
Scientists from Laval University and the University of Lethbridge have succeeded in reversing certain cognitive manifestations associated with Alzheimer’s in an animal model of the disease.
Their results were published in the scientific journal Brain.
“Even if the demonstration remains to be done in humans, we believe that the mechanism that we have brought to light constitutes a very interesting therapeutic target, because it is not limited to slowing down the progression of the disease, but it makes it possible to partially restore certain cognitive functions”, comments the head of the study, Yves De Koninck, professor at the Faculty of Medicine and researcher at the CERVO Research Center of Laval University, via press release.
Effects before diagnosis
Previous studies have shown that even before Alzheimer’s symptoms appear, brain activity is disrupted in people who will develop the disease.
“There is neuronal hyperactivity and a disorganization of signals in the brain, explains the researcher, in the same communication to the media. Our hypothesis is that a mechanism that regulates neuronal activity, specifically the one responsible for inhibiting neural signals, is disrupted.”
The main inhibitor of neural signals in the human brain is the neurotransmitter GABA.
It works in close collaboration with a cotransporter, KCC2. It is an ion pump, located in the cell membrane, which circulates chloride ions and potassium ions between the interior and exterior of neurons.
Maintaining an ion pump located in the cell membrane of neurons would slow down or reverse the pathology.
“When there is a loss of KCC2 in the cell membrane, this can lead to neuronal hyperactivity, adds Professor De Koninck, in a press release. A study has already shown that KCC2 levels were reduced in the brains of deceased people who had suffered from Alzheimer’s. This gave us the idea to examine the role of KCC2 in an animal model.”
Promising effects in mice
The scientists used a line of mice that express a manifestation of Alzheimer’s.
They found that when these mice reached four months of age, KCC2 levels decreased in two regions of their brains, namely the hippocampus and the prefrontal cortex. These two regions are also affected in people who suffer from Alzheimer’s.
In light of these results, the research team used a molecule developed in their laboratory, CLP290, an activator of KCC2 which prevents its reduction.
In the short term, the administration of this molecule to mice which already had reduced levels of KCC2 led to an improvement in their spatial memory and their social behaviors.
In the long term, CLP290 protected them once morest a decrease in cognitive abilities and once morest neuronal hyperactivity.
“Our results do not imply that the loss of KCC2 causes Alzheimer’s, insists Yves De Koninck. On the other hand, it seems to cause an ionic imbalance leading to neuronal hyperactivity that can lead to the death of neurons. This suggests that preventing the loss of KCC2 might slow and possibly even reverse some manifestations of the disease.”
For various reasons, CLP290 cannot be used in humans. Researcher De Koninck’s team is looking for other KCC2 activating molecules that would be well tolerated by people suffering from Alzheimer’s. (CP/IJL)
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