Brain: Restoring KCC2 in Neurons Holds Promise for Improving Cognitive Performance of Alzheimer's Disease

In a recent study, researchers from Laval University in Canada and the University of Lethbridge successfully reversed certain cognitive deficits in an Alzheimer's disease animal model. Their findings were published online on August 8, 2023, in the Brain journal under the title "Restoring neuronal chloride extrusion reverses cognitive decline linked to Alzheimer's disease mutations."

Prior research has indicated that even before the onset of Alzheimer's disease symptoms, brain activity is disrupted, setting the stage for the disease. Neuronal activity in the brain becomes hyperactive, leading to disrupted signaling. The primary inhibitory agent for neuronal signals in the brain is the neurotransmitter GABA, which closely collaborates with the co-transporter protein KCC2. KCC2 is an ion pump located on the cell membrane, responsible for cycling chloride and potassium ions inside and outside neurons. Maintaining this ion pump on the neuronal cell membrane may help slow or reverse the pathology of Alzheimer's disease.

In addition, the loss of KCC2 in the cell membrane leads to neuronal overexcitation. Previous studies have shown a significant reduction in KCC2 levels in the brains of deceased Alzheimer's patients, sparking our interest in studying the role of KCC2 in an Alzheimer's disease animal model.

Although this has not been confirmed in humans yet, the mechanism discovered is a highly intriguing therapeutic target. It holds the potential not only to slow down the progression of this disease but also to partially restore certain cognitive functions.

Encouraging Results from Mouse Experiments

To delve deeper into this mechanism, the researchers utilized a mouse model that mimicked Alzheimer's disease symptoms. They observed that when these mice reached four months of age, the levels of KCC2 in their brains, particularly in the hippocampus and frontal cortex, were reduced. These are the same regions affected in Alzheimer's disease patients.

Fig.2 KCC2 Changes in 5xFAD and AppNL-G-F mice. (From Brain, 2023, doi:10.1093/brain/awad250)

Given these results, the researchers turned their attention to a molecule they had developed in their laboratory, known as CLP290. CLP290 is an activator of KCC2 that prevents its depletion. Administering CLP290 to mice with reduced KCC2 levels in the short term resulted in improvements in their spatial memory and social behavior. In the long run, CLP290 has the potential to protect them from the effects of declining cognitive abilities and neuronal overexcitation.

It is important to note that, at present, CLP290 cannot be used in humans. Professor De Koninck and his team are actively seeking other KCC2 activators that can be well-tolerated by Alzheimer's disease patients and are also exploring the impact of existing drugs on KCC2, which could expedite the development of this new therapeutic approach for the disease.