KCC2 in Alzheimer's Disease
The challenge with most identified mechanisms of disease is that they are not close enough to root causes to be highly influential on the progression of the condition. Particularly in the case of neurodegenerative diseases such as Alzheimer's disease, the condition is very complex, and there is much to be discovered about how dysfunction progresses. That doesn't mean that any given aspect of that progression will prove to be useful enough to make the jump from improvements shown in animal models to a basis for therapy in humans. There are many discoveries in the history of Alzheimer's research that have appeared to be as interesting as the work noted here.
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. 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. "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."
Scientists used mice 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. "Our results do not imply that the loss of KCC2 causes Alzheimer's disease. On the other hand, it does appear to cause an ionic imbalance leading to neuronal hyperactivity that can lead to neuronal death. This suggests that by preventing the loss of KCC2, we could slow down and perhaps even reverse certain manifestations of the disease."