A breakthrough has been achieved by researchers hailing from Laval University and the University of Lethbridge, who managed to reverse specific cognitive impairments associated with Alzheimer’s disease in an animal model. Their significant findings have been recently documented in the journal Brain.
Study leader Yves De Koninck, a professor at Laval University’s Faculty of Medicine and a researcher at the CERVO research center, expressed optimism about the therapeutic potential of their discovery. He stated, “While we are yet to validate these findings in humans, we believe that the mechanism we’ve unveiled presents a compelling therapeutic target. It not only decelerates the disease’s progression but also partially restores certain cognitive functions.”
Prior research has indicated that even before Alzheimer’s symptoms surface, there is a disruption in brain activity in individuals who eventually develop the disease. De Koninck elaborates, “There is excessive neuronal activity and disarray in signal transmission within the brain. Our hypothesis is that a mechanism responsible for regulating neuronal activity, specifically the one that inhibits neuronal signals, is compromised.”
In the human brain, the principal inhibitor of neuronal signals is the neurotransmitter GABA, which collaborates closely with a cotransporter called KCC2. KCC2, situated in the cell membrane, regulates the flow of chloride and potassium ions between the interior and exterior of neurons. Sustaining the presence of this ion pump in the neuron’s cell membrane could potentially impede or reverse the disease’s pathological processes.
De Koninck further explains, “A reduction of KCC2 in the cell membrane can lead to neuronal hyperactivity. A previous study had already indicated reduced KCC2 levels in the brains of deceased Alzheimer’s patients. This led us to investigate the role of KCC2 in an animal model of Alzheimer’s disease.”
To investigate, scientists utilized mouse lines that exhibited Alzheimer’s disease-related manifestations. Their research revealed that when these mice reached four months of age, KCC2 levels decreased in two key brain regions: the hippocampus and the prefrontal cortex—regions commonly affected in Alzheimer’s patients.
In response to these findings, the researchers turned to CLP290, a molecule developed in their laboratory known to activate KCC2 and prevent its depletion. Administering this molecule to mice with reduced KCC2 levels resulted in short-term improvements in their spatial memory and social behavior. Over the long term, CLP290 provided protection against cognitive decline and neuronal hyperactivity.
De Koninck emphasizes, “Our results do not suggest that the loss of KCC2 causes Alzheimer’s disease. However, it does appear to induce an ionic imbalance that leads to neuronal hyperactivity, potentially culminating in neuronal death. This suggests that by preventing KCC2 loss, we could potentially slow down or even reverse certain disease manifestations.”
Although CLP290 cannot be used in humans for various reasons, Professor De Koninck’s team is actively searching for other KCC2-activating molecules that can be well-tolerated by individuals with Alzheimer’s.
He notes, “We have developed new molecules currently undergoing evaluation in our laboratory. In parallel, we are exploring the effects of drugs used for purposes other than Alzheimer’s in humans, aiming to assess their impact on KCC2. Repurposing existing drugs could expedite progress in this novel therapeutic avenue.”
The study published in Brain includes other contributing researchers from Laval University, namely Iason Keramidis, Julien Bourbonnais, Feng Wang, Dominique Isabel, Marie-Eve Paquet, Romain Sansonetti, Annie Barbeau, Lionel Froux, and Antoine Godin. Researchers from the University of Lethbridge, including Brendan McAllister, Edris Rezaei, Phil Degagne, Mojtaba Nazari, Samsoon Inayat, and Majid Mohajerani, also played vital roles in this groundbreaking research.