What are the biological mechanisms of APOE that may impact the onset of Alzheimer’s?
Scott Ayton, Ph.D.
Florey Institute of Neuroscience and Mental Health
The apolipoprotein E (APOE) gene provides instructions for making the ApoE protein that is thought to help carry fats throughout the body. A variation in the APOE gene, called APOE-e4, is thought in some populations to impact a person’s risk of developing Alzheimer’s. However, the biological mechanism by which APOE-e4 increases the risk of developing Alzheimer’s is still unclear.
Dr. Scott Ayton and colleagues have discovered a link between people with the APOE-e4 genetic variation and the presence of high levels of iron in the brain. Studies show that too much high levels of iron in the brain can trigger a type of cell death pathway known as “ferroptosis” that can cause brain damage. Based on these findings, Dr. Ayton believes that in a cognitively unimpaired state, the APOE gene may protect the brain from ferroptosis, whereas in Alzheimer’s, genetic variations in APOE might change this function and make brain cells more vulnerable to ferroptosis.
Dr. Ayton’s team will study the biological mechanisms that may be altered by the APOE genetic variations that could lead to an increased risk of Alzheimer’s. First, the researchers will identify specific proteins on the surfaces of brain cells in laboratory dishes. They will study how the surface proteins interact with ApoE to understand how the ApoE protein is modified in different ways that may impact ferroptosis.
Dr. Ayton and colleagues will also create a new mouse model to study the biological mechanism by which the ApoE protein may impact ferroptosis. They will genetically engineer mice to lack both APOE and a gene called GPX4 that regulates ferroptosis. Previous studies show that mice without GPX4 experience rapid brain cell death. To understand whether APOE is protective for brain cells, Dr. Ayton will study if these mice which lack APOE (in addition to lacking GPX4) exhibit worsening and accelerating brain cell damage.
If successful, this study could help understand the underlying biology of brain cell death in Alzheimer’s as well as may help identify key proteins involved in ferroptosis that might be potential therapeutic targets against the disease.
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