Scientists at Université Laval and the University of Lethbridge have succeeded in reversing certain cognitive manifestations associated with Alzheimer's disease in an animal model of the disease. Their results have been published in the scientific journal Brain.
Previous studies have shown that even before Alzheimer's symptoms appear, brain activity is disrupted in people who go on to develop the disease.
"There is neuronal hyperactivity and signal disorganization in the brain. Our hypothesis is that a mechanism that regulates neuronal activity, more specifically the one responsible for inhibiting neuronal signals, is disrupted," explains the researcher.
"A loss of KCC2 in the cell membrane can lead to neuronal hyperactivity. One study has already shown that KCC2 levels were reduced in the brains of deceased Alzheimer's patients. This gave us the idea of examining the role of KCC2 in an animal model of Alzheimer's disease," adds the researcher.
To do this, scientists used mouse lines expressing a manifestation of Alzheimer's disease. The researchers found that when these mice reached the age of four months, KCC2 levels decreased in two regions of their brains: the hippocampus and the prefrontal cortex. These two regions are also affected in people suffering from Alzheimer's disease.
In light of these results, the researchers turned to a molecule developed in their laboratory, CLP290, a KCC2 activator that prevents its depletion. In the short term, the administration of this molecule to mice that already had reduced KCC2 levels improved their spatial memory and social behaviour. In the long term, CLP290 protected them against cognitive decline and neuronal hyperactivity.
For various reasons, CLP290 cannot be used in humans. Professor De Koninck's team is searching for other KCC2-activating molecules that would be well tolerated by Alzheimer's sufferers.
"We have developed new molecules which are currently being evaluated in our laboratory. In parallel with this research, we are testing drugs that are used for purposes other than Alzheimer's in humans, in order to assess their effects on KCC2. Repositioning an existing drug would accelerate work on this new therapeutic avenue," emphasizes the researcher. (IB/NW)
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