2022 Alzheimer's Association Research Fellowship (AARF)

Systematic Investigation of the Impact of AD Risk Genes on Microglia States

How do known risk genes for Alzheimer’s impact the activity and function of immune cells in the brain?

Amanda McQuade, Ph.D.
University of California, San Francisco
San Francisco, CA - United States

Background

The immune system is complex and works to maintain our overall health. Microglia are the primary immune cells in the brain, and work to maintain healthy nerve cells by removing unwanted molecules in the brain, along with other functions. Problems within the immune system, including increased activity of microglia, can lead to brain inflammation, which is common in individuals with Alzheimer’s.

Another factor that can contribute to Alzheimer’s is an individual's genes (coded for in their DNA). Current research focuses on how genes interact with other factors, like the immune system, to increase or decrease one's risk of Alzheimer’s. Many of the genes identified related to risk have been linked to the microglia. Understanding how the microglia and risk genes interact will help increase the understanding of the unique role they play in Alzheimer’s.

Research Plan

Dr. Amanda McQuade and colleagues will study whether previously identified Alzheimer’s  risk genes impact disease progression through their impact on microglia activity. The researchers will use a specialized type of stem cell collected from adult human tissue called hiPSCs (human induced pluripotent stem cells). These hiPSCs are from adult cells that can be reprogrammed into any type of cell in the human body, including microglia. Using microglia generated from these cells, the research team will study the role that 100 specific risk genes may play in microglia’s activity. By turning different risk genes “on” and “off” through a gene editing technique called CRISPR (which allows genes to be manipulated for increased or decreased activity), Dr. McQuade and colleagues will study how these genes may influence microglia activity and function. Additionally, the research team will evaluate the therapeutic potential of regulating microglia activity in special genetically engineered Alzheimer’s-like mice that have human microglia cells in their brains.

Impact

This research may provide information on the role microglia play in Alzheimer’s and improve our understanding of how this biology intersects with known genes that increase or decrease risk. A greater understanding of microglia activity in Alzheimer’s may contribute to the development of novel therapies.