Maintaining an ion pump located in the cell membrane of neurons could slow down or reverse the pathology.
Text by Jean Hamann – Université Laval nouvelles
A team of researchers led by Dr. Yves De Koninck Professor at Université Laval and researcher at Université Laval’s CERVO research centre, reports in the journal Brain that they have succeeded in reversing certain cognitive manifestations associated with Alzheimer’s in an animal model of the disease. “Although this has yet to be demonstrated in humans, we believe that the mechanism we have identified constitutes a very interesting therapeutic target because it is not limited to slowing down the progression of the disease, but also makes it possible to partially restore certain cognitive functions,” comments Dr. De Koninck.
Previous studies have shown that even before the symptoms of Alzheimer’s appear, brain activity is disrupted in people who go on to develop the disease. There is neuronal hyperactivity and a disorganisation of signals in the brain,” explains the researcher. Our hypothesis is that a mechanism that regulates neuronal activity, more specifically the one responsible for inhibiting neuronal signals, is disrupted.”
The main inhibitor of neuronal signals in the human brain is the neurotransmitter GABA. It works in close collaboration with a cotransporter, KCC2. This is an ion pump, located in the cell membrane, which circulates chloride and potassium ions between the inside and outside of neurons,” explains Professor De Koninck.
“Whenever there is a loss of KCC2 in the cell membrane, the level of chloride ions increases inside neurons, and GABA-mediated inhibition is disrupted,” he continues. This can lead to neuronal hyperactivity. A study has already shown that levels of KCC2 were reduced in the brains of deceased people who had suffered from Alzheimer’s disease. This gave us the idea of examining the role of KCC2 in an animal model of Alzheimer’s disease”.
To do this, the researchers used a line of mice that express one of the two main manifestations of Alzheimer’s in humans: the formation of amyloid plaques in the brain. In this mouse model of the disease, plaques appear in the brains their abundance increases with age.
The researchers found that, when the mice reached 4 months of age, KCC2 levels decreased in two regions of their brains. These two regions, the hippocampus and the prefrontal cortex, are also affected in people suffering from Alzheimer’s disease. “The greater the loss of KCC2, the more amyloid plaques the mice had”, notes Professor De Koninck.
In light of these results, the researchers used a molecule developed in their laboratory, CLP290, a KCC2 activator which prevents its depletion. Short-term, administration of this molecule to mice that already had reduced levels of KCC2 improved their spatial memory and social behaviour. Long-term, CLP290 protected them against a reduction in cognitive capacity and neuronal hyperactivity.
“These results do not imply that the loss of KCC2 causes Alzheimer’s disease,” insists Professor De Koninck. “However, it does appear to cause an ion imbalance leading to neuronal hyperactivity that can lead to the death of neurons. This suggests that by preventing the loss of KCC2, we could slow down and perhaps even reverse certain manifestations of the disease”.
For various reasons, CLP290 cannot be used in humans. Professor De Koninck’s team is looking for other KCC2-activating molecules that would be well tolerated by Alzheimer’s sufferers. “We have developed new molecules that are currently being evaluated in our laboratory. In parallel with this research, we are testing drugs used for purposes other than Alzheimer’s in humans to assess their effects on KCC2. Repositioning an existing drug would accelerate work on this new therapeutic avenue,” says the researcher.
The other authors of the study published in Brain are Iason Keramidis, Julien Bourbonnais, Feng Wang, Dominique Isabel, Marie-Eve Paquet, Romain Sansonetti, Annie Barbeau, Lionel Froux and Antoine Godin, from Laval University, and Brendan McAllister, Edris Rezaei, Phil Degagne, Mojtaba Nazari, Samsoon Inayat and Majid Mohajerani, from the University of Lethbridge.
Read the original story on the Université Laval website
Original Research article in the Journal Brain (Open Access): Iason Keramidis, Brendan B McAllister, Julien Bourbonnais, Feng Wang, Dominique Isabel, Edris Rezaei, Romain Sansonetti, Phil Degagne, Justin P Hamel, Mojtaba Nazari, Samsoon Inayat, Jordan C Dudley, Annie Barbeau, Lionel Froux, Antoine G Godin, Majid H Mohajerani, Yves De Koninck, Restoring neuronal chloride extrusion reverses cognitive decline linked to Alzheimer’s disease mutations, Brain, 2023;, awad250, https://doi.org/10.1093/brain/awad250
