Assessing the Links Between the Ms4a Risk Genes, Microglia and Alzheimer’s Disease

Alzheimer’s disease (AD) is caused by progressive changes in brain cells that culminate in memory loss, confusion, difficulty completing tasks, withdrawal, mood changes and ultimately death. The main cell type affected in the brain by Alzheimer’s disease is called the neuron, which is primarily responsible for processing information and generating action. Alzheimer’s disease damages neurons and the connections between neurons required to pass information along; as the ability of the brain to process information declines, so does the ability to care for one’s self and to interact with loved ones. Although the ultimate target of Alzheimer’s disease is the neuron, recent advances in genetics have suggested that a different type of cell might be the cause. These cells are called glia, which for many years were thought to be merely the “glue” that holds the brain together. It is now thought that glia may act to protect or harm neurons, and in doing so, may influence the odds of developing Alzheimer’s disease and its associated progression. Here we focus on a set of genes, called the MS4As, that seems to have a surprising degree of influence on a given person’s chances of developing Alzheimer’s disease later in life. Interestingly, these genes seem to act in a subset of glial cells called microglia, rather than neurons, consistent with microglia playing an important role in disease initiation or progression. In order to make the link between the MS4As and Alzheimer’s disease, we propose experiments to explore how the MS4A genes influence both the normal function of microglia and the function of microglia in the context of Alzheimer’s disease. Further, we propose to build tools that will help us to build new drugs that target the MS4A genes. Results from these studies will teach us how a gene family that acts in microglia might influence the risk that a person will develop Alzheimer’s disease. Our experiments also may identify a new set of promising targets that could be the substrate for future drug development.