Neurotoxic Reactive Astrocytes in Alzheimer’s Disease

The brain is composed of neurons that transmit signals to enable thought, memory and motion. The brain also contains a type of cell that outnumbers neurons 2-to-1 called glial cells, which provide support to neurons. Recent genetic association studies have implicated many disease-associated genes in patients with Alzheimer’s disease that almost exclusively are associated with glial cells. Astrocytes, a specific type of glial cell involved in nutrient delivery to neurons, are the most abundant cells in the brain. Astrocytes provide the environment necessary for neurons to correctly wire together and transmit signals. During diseases like Alzheimer’s disease, astrocytes can become reactive—switching from a supportive state to a diseased state, in which neuron-killing toxins are secreted. In both animal models of AD and in human patients, our research recently has localized the toxic reactive state of astrocytes to regions of dead and dying neurons. This research will employ a powerful technique called single-cell sequencing technology to increase the resolution at which changes in gene expression are observed at the cellular level. This technology will be used to determine how many populations of reactive astrocytes exist in the human brain, and how this cell plays a role in the initiation and progression of Alzheimer’s disease by becoming neurotoxic. Results of this study will provide much-needed insights into basic astrocyte biology in the context of AD, as well as the identification of new targets for development of future therapies.