Background

Within the brain, cells communicate by sending signals that either enhance or dampen the activity of other cells. Balancing these excitatory and inhibitory signals is vital for the brain to function. Many components maintain this balance, but one key player is the protein KCC2. As levels of KCC2 are reduced in the brain, the balance shifts excessively toward excitation, diminishing the ability of the brain to process information. Importantly, low KCC2 levels have been observed in the brains of Alzheimer’s disease (AD) patients, and at a much earlier age, in mice engineered to develop AD-like symptoms. However, researchers have yet to examine whether reduced KCC2 function is a cause of the cognitive impairments, such as memory loss, observed in healthy elderly individuals and,

more profoundly, in patients with AD. If it is, by using drugs designed to boost the function of KCC2, it should be possible to prevent, reduce, or perhaps even reverse this cognitive decline.

Research Plan

Our goal is to investigate this possibility, using techniques that allow us to record brain waves and to peer into the brain to observe its function at multiple levels, from widescale neural networks to individual cells. We will determine where and when the disease process impacts KCC2 levels using mice that develop AD-like plaques and tangles in their brains. Using these AD mouse models, we will test whether treating KCC2-enhancing drugs improves brain function and eliminates cognitive decline.

Impact

These studies will determine if KCC2-enhancing drugs hold promise as a treatment for AD, a malady that imposes a massive burden on patients, families, and society, but for which treatments can halt disease progression are sorely lacking.