APP modulates KCC2 expression and function in hippocampal GABAergic inhibition

Alzheimer’s disease is the most common form of dementia. One of the hallmarks of the disease is the formation of sticky protein clumps called amyloid plaques in the brain. These plaques are formed from specific fragments of a protein called APP. The intact form of APP is essential for synapses (the junctions across which neurons transmit signals) to form and work correctly. The hippocampus is one of the first brain regions to be affected in Alzheimer’s disease and is important for forming memories and emotions. In the hippocampus, GABAA receptors at synapses normally tightly regulate synaptic signaling by reducing the ability of the receiving neuron to respond, but this inhibition is disrupted in Alzheimer’s disease. Studies suggest that APP can affect how GABAA receptors transmit signals, but it is not known how it does so. One possibility is that APP regulates a protein called KCC2 that helps to maintain the inhibitory effect of GABAA receptors. To investigate this, Chen et al. genetically modified mice to lack the gene that produces APP. These mice had a lower level of KCC2 in their hippocampus than normal mice, and their GABAA receptors were less able to inhibit synaptic signaling. Further experiments demonstrated that APP physically interacts with KCC2 and maintains normal levels of the protein by preventing it from being chemically modified and degraded. Chen et al. also showed that treating mice that lack APP with specific compounds can restore KCC2 activity and return the behavior of synaptic GABAA receptors to normal. Future studies in mice (and eventually people) that exhibit symptoms of Alzheimer's disease will help to determine whether KCC2 is important in the development of the disease. If so, modifying the levels of the KCC2 protein in the brain could potentially help to slow down memory loss in Alzheimer’s disease.