2023 Alzheimer's Association Research Grant (AARG)
The Mechanisms Driven by Microglial FOXO3 Underlying AD Progression
How might gene levels inside immune cells change during Alzheimer’s?
Jihye Paik, Ph.D.
Weill Medical College of Cornell University
New York, NY - United States
Background
Microglia are the primary immune cells of the brain. They play a major role in helping to maintain healthy nerve cells, in part by removing unwanted material from the brain. Previous research Dr. Jihye Paik and colleagues has shown that levels of certain proteins inside microglia are elevated during Alzheimer’s. They found particularly high levels of one of protein, called FOXO3, inside brain tissue samples from individuals who had Alzheimer’s and in the brains of genetically engineered Alzheimer’s-like mice. It’s not yet clear how elevated FOXO3 levels might contribute to Alzheimer’s progression.
Research Plan
Dr. Paik’s team will determine if lowering FOXO3 levels in microglia might improve Alzheimer’s-like symptoms in mice and how FOXO3 might contribute to problems with microglia that occur during Alzheimer’s. The researchers will genetically engineer Alzheimer’s-like mice to lack the gene encoding FOXO3 inside microglia. Then, the researchers will assess mouse cognition and measure brain cell function and levels of beta-amyloid, a hallmark protein of Alzheimer’s, in the brains of the mice. The researchers will then measure gene levels inside microglia collected from the mice. Dr. Paik’s goal is to identify any changes in other genes that might occur as a result of lowering FOXO3 levels, which could reveal a broader biological role of FOXO3. The researchers will compare their findings to genetic analyses performed inside human cells that also lack FOXO3. They will determine whether microglia collected from Alzheimer’s-like mice lacking FOXO3 might still be able to help perform their important role in the brain: clearing unwanted material.
Impact
Results from this study will help explore the role of FOXO3 in Alzheimer’s and lay the foundation for therapeutic strategies designed to restore healthy microglia function. This study may also reveal gene networks that might contribute to changes in FOXO3 or microglia that occur during Alzheimer’s.