2022 Alzheimer's Association Research Grant (AARG)

Investigate the Cellular Response to Diverse Types of Amyloid Beta Deposits

How do different types of beta-amyloid deposits impact surrounding brain cells in Alzheimer’s?

Abhisek Mukherjee, Ph.D.
University of Texas Health Science Center at Houston
Houston, TX - 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. Individuals with Alzheimer’s typically experience brain inflammation. This is caused by changes in the immune system, including increased activity of microglia, which can damage nearby nerve cells. Recent studies have suggested 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. 

Beta-amyloid plaques can be made up of different versions of the same protein that has been cut at different spots. Each type has its own specific properties, and the amount present can change how the nerve cells and other cells, such as microglia, may be affected. However, exactly what these differences are is currently unknown.

Research Plan

Dr. Abhisek Mukherjee and colleagues recently showed that they could label two different versions of beta-amyloid in human brain tissue. Using this technique, the researchers will study how these different beta-amyloid proteins may impact nearby brain cells in Alzheimer’s. The team will study brain tissue from individuals who had Alzheimer’s and cognitively unimpaired individuals. They will investigate whether the types of beta-amyloid have different impacts on the health and activity of nearby cells. This will help produce a map of distinct types of cells and their activity close to different plaques. 

In addition, Dr. Mukherjee and colleagues will study the biological mechanisms underlying the microglia’s responses in the brain. The researchers will add different types of beta-amyloid to microglia grown from induced pluripotent stem cells (iPSCs), a type of stem cell engineered from adult human skin cells and then “reprogrammed” into brain cells. They will also add the different types of beta-amyloid to specialized structures known as cerebral organoids that may more accurately model the human brain. These structures are created in the laboratory from iPSCs. When grown in a laboratory dish under the right conditions, a group of brain cells can mimic the structure and function of the brain tissue.

Impact

The results may contribute to our understanding of how disease-related brain changes in the brain impact other brain cells.