Axonal Transcription Factor Complexes in Alzheimer’s Disease

Background Nerve cells use long, thread-like extensions to interact with other brain cells. These extensions, called axons, can span multiple brain regions and serve as conduits for cell signals. Nerve cells sense changes in their environment, such as an increase in beta-amyloid protein during Alzheimer’s disease, with the help of these long cellular projections. In this way, axons serve as one of the earliest sensors of brain changes associated with Alzheimer’s. When axons encounter stimuli like beta-amyloid, they transmits signals along these extensions back to the cell nucleus—much like fingers send signals back to our brains. The nucleus contains one’s DNA for controlling which genes are expressed or repressed. Many of the signals, like beta-amyloid, activate proteins, called transcription factors that bind to and control nerve cell DNA. Some signals activate transcription factors that can destroy nerve cells. Interfering with harmful signals could be one way to limit nerve cell death that occurs during Alzheimer’s disease. Research Plan Cláudio Gouveia Roque, Ph.D. and colleagues will study how two transcription factors are activated inside nerve cell axons, and how these factors interact to damage nerve cells during Alzheimer's disease. Previous research by the team has shown that Alzheimer's brain changes activate the transcription factor ATF4. The new study will build on this information to understand how activated ATF4 functions as part of a protein complex to cause the nerve cell death observed in the disease. First, the researchers will identify brain regions and disease stages in which this protein complex levels are highest, using brain tissue samples from mice and people who had Alzheimer's. Second, the team will study which genes ATF4 protein complexes regulate in the nucleus. These experiments will help explain how transcription factors activated by Alzheimer's brain changes can alter DNA regulation. Finally, Dr. Gouveia Roque and colleagues will design novel small molecules to disrupt this specific protein interaction from occurring. Using nerve cells grown in laboratory dishes researchers will determine if interrupting these interactions will prevent or slow nerve cell degeneration.