2024 Alzheimer's Association Research Grant (AARG)

Role of the transcription factor PU.1 in Alzheimer's Disease

What is the role of PU.1 Alzheimer’s disease?

Simone Brioschi, Ph.D.
Washington University in St. Louis
St. Louis, MO - United States

Background

Recent studies have identified the protein PU.1 as a key regulator of the immune response in the brain during Alzheimer’s. The PU.1 protein is only found inside microglia, which are the most common immune cells in the brain. Microglia help remove toxins from the brain, including high levels of beta-amyloid that often accumulate into plaques as a hallmark of Alzheimer’s disease. 

Previous studies suggest that increased levels of PU.1 can lead to inflammatory damage in the brain, as seen in multiple laboratory models of brain diseases. Additional studies suggest that genetic variations that reduce PU.1 levels may delay Alzheimer’s disease onset. However, it is not well understood what the role of PU.1 is in microglia.

Scientists often remove a protein to help understand its function inside cells, however a challenge to studying PU.1 is that removing it is lethal to mice. In preliminary studies, Dr. Simone Brioschi and colleagues have found a way to genetically remove PU.1 in embryonic mice.

Research Plan

Dr. Brioschi and colleagues will study what happens to microglia in mice when PU.1 has been removed. Using genetically engineered mice lacking PU.1, the team will assess microglia development. They will also use genetic tools to remove PU.1 from genetically-engineered Alzheimer’s-like mice to study the impact of PU.1 loss on beta-amyloid accumulation. Moreover, they will study how microglia respond to beta-amyloid accumulation in these mice, as well as how other immune cells respond.

Impact

This study aims to better understand the role of PU.1 in Alzheimer’s. The work may also establish new laboratory models and techniques that can be used by other researchers in the field of Alzheimer’s disease.