2024 Alzheimer's Association Research Grant (AARG)
The Role of APOE4 in Synaptic Mitochondrial Dysfunction
How do genetic variations linked to Alzheimer’s impact the energy centers in brain cell connections?
Kelly Stauch, Ph.D.
University of Nebraska University Medical Center
Omaha, NE - United States
Background
The apolipoprotein E (APOE) gene provides instructions for making ApoE, a naturally occurring protein believed to help carry fats, such as cholesterol, throughout the body. There are several genetic variations of APOE, including APOE-e2, APOE-e3 and APOE-e4. Individuals who possess APOE-e4 are at an increased risk for developing Alzheimer’s, compared with those who possess other APOE variations. Scientists are trying to understand the exact biological mechanisms linking APOE-e4 and Alzheimer’s risk.
In preliminary work, Dr. Kelly Stauch studied the connections between brain cells, called synapses, in mice. Dr. Stauch and colleagues found that mice with the APOE-e4 gene seem to have problems with the energy centers (known as mitochondria) in their synapses.
Research Plan
Dr. Stauch will use genetically engineered mice with Alzheimer’s-like brain changes to study how the APOE-e4 gene affects the fats (like cholesterol) in the mitochondria within synapses. Dr. Stauch and colleagues will also determine how these changes might relate to a protein called Tau, which clumps into “tangles” in the brain, one of the characteristic features of Alzheimer's disease.
Moreover, the research team will study how the APOE-e4 gene affects the protein composition of the mitochondria within synapses. They will study what kind of molecular changes occur within the synapses’ mitochondria that may account for the disease-specific changes. To do this, they’ll use special tests to measure how these energy centers are working and what's happening inside.
Impact
Dr. Stauch’s research could provide valuable insights into the role of the APOE-e4 gene in Alzheimer's disease. It may also help understand how APOE-e4 affects mitochondrial function in brain cells.