2024 Alzheimer's Association Research Grant (AARG)
DevoAPOE: Developmental APOE Controls Adult Microglia Function
How do certain genetic variations change the function of immune cells in the brain?
Amanda Sierra, Ph.D.
Achucarro Basque Center for Neuroscience
Leioa, Spain
Background
Microglia are the primary immune cells in the brain. They play a major role in helping to maintain healthy nerve cells. Recent research suggests that Alzheimer’s can change the ability of microglia to perform this important function.
One genetic risk factor for Alzheimer’s is apolipoprotein E (APOE), a gene with several variations, including APOE-e2, APOE-e3 and APOE-e4. Studies show that microglia containing the APOE-e4 variation are less able to perform their protective functions in the brain. Microglia with APOE-e4 may also grow and develop differently than microglia without this variation. More research is needed to understand exactly how APOE variations change microglia and contribute to brain changes associated with Alzheimer’s.
Research Plan
Dr. Amanda Sierra and colleagues will determine the role of APOE in human microglia growth and function using a laboratory model they call DevoAPOE. This model involves a specialized type of stem cell called induced pluripotent stem cells (iPSCs). These are adult human skin cells that can be “reprogrammed” into any type of cell in the body, including microglia, and are grown in laboratory dishes. Dr. Sierra’s team will grow iPSCs into microglia containing either APOE-e3 or APOE-e4 genetic variations. Then, they will transplant these cells into the brains of mice.
The researchers will examine brain tissue samples from the mice and perform genetic analyses to understand how the transplanted microglia developed over time. The researchers will also inject mice containing transplanted microglia with beta-amyloid, a protein that can accumulate in the brains of people with Alzheimer’s. The researchers will assess mouse cognition, and then again study brain tissue samples from the mice to measure how well the microglia were able to remove beta-amyloid from the brain. This will help Dr. Sierra and team understand how APOE-e3 and APOE-4 genetic variations might affect these important immune cells in the brains of mice.
Impact
This study could provide a deeper understanding of how microglia develop in the brains of individuals at a higher risk of developing Alzheimer’s. Results from this study could connect changes in microglia growth and development to genetic variations known to play a role in Alzheimer’s. These findings might also uncover genetic mechanisms that contribute to immune cell function in the brain.