2022 Zenith Fellows Award Program (ZEN)

Controlling Microglia States for Therapeutic Benefit in Alzheimer’s Disease

What are the biological mechanisms underlying changes in brain immune cells associated with Alzheimer’s?

Martin Kampmann, Ph.D.
University of California, San Francisco
San Francisco, CA - United States

Background

The immune system is complex and serves to maintain our overall health. In the brain, the immune system specifically serves to maintain healthy nerve cells. Microglia are the primary immune cells of the brain, and they play a major role helping to maintain healthy nerve cells. Microglia are also implicated in brain diseases, including Alzheimer’s. 

Individuals with Alzheimer’s typically experience brain inflammation caused by changes in the immune system, including increased activity of microglia, which can damage nearby nerve cells. Recent studies have shown that overly active microglia tend to gather in areas of the brain susceptible to other dementia-related brain changes, such as beta-amyloid plaques and tau tangles, two hallmark brain changes associated with Alzheimer’s. These findings suggest microglia may play multiple roles in the development of Alzheimer’s.

Dr. Martin Kampmann and colleagues identified a group of microglia seen with brain diseases called interferon-responsive microglia. These microglia increase in number during aging and in several brain diseases. However, it is unclear if they are a necessary response to aging or if they contribute to nerve cell death and cognitive decline. 

Research Plan

Dr. Kampmann and team developed a new lab technique based on the gene editing technology known as CRISPR. The new technique allows researchers to screen the entire genome (all of the genetic material) of a cell for potential drug targets. Dr. Kampmann and colleagues will use this new technique on a specialized type of stem cell collected from adult human tissue called induced pluripotent stem cells (iPSCs). iPSCs can be re-programmed to grow into any type of cell in the human body, including nerve cells and microglia. 

First, the researchers will study interferon-responsive microglia created from iPSCs and characterize how they function. Next, they will use their novel genome-screening technique to discover genes that impact whether individual microglial cells are interferon-responsive microglia or not. Finally, to investigate the therapeutic potential of targeting this group of microglia, Dr. Kampmann and colleagues will modulate interferon-responsive microglia in two kinds of genetically engineered Alzheimer’s-like mice.

Impact

This study may uncover biological pathways underlying the involvement of brain immune cells in brain diseases. The findings may lead to new therapeutic avenues for the prevention or treatment of Alzheimer’s and other diseases.