2021 Alzheimer's Association Research Fellowship (AARF)

APOE4-Regulation of Neutrophil-Microglia Crosstalk in Alzheimer’s Disease

Does the interaction between immune cells in the brain impact brain changes observed in Alzheimer’s?

Neta Rosenzweig, Ph.D.
Brigham and Women's Hospital
Boston, MA - United States

Background

The apolipoprotein E (APOE) gene provides instructions for making ApoE, a naturally occurring protein believed to help carry fats throughout the body. There are several genetic variations of APOE, including APOE-e2, APOE-e3 and APOE-e4. The variation APOE-e4 is thought in some populations to impact a person’s risk of developing Alzheimer’s. Scientists are trying to understand the exact biological mechanisms that may increase the risk of developing Alzheimer’s in individuals with the APOE-e4 genetic variation.

Microglia are the primary immune cells of the brain, where they help maintain healthy nerve cells. Individuals with Alzheimer’s typically experience brain inflammation caused by dysregulation of the immune system, including increased activity of microglia, which can damage the nearby nerve cells. Dr. Neta Rosenzweig and colleagues previously showed that genetic variations of APOE may be associated with regulating the activity of microglia in Alzheimer’s. However, it is unknown how other types of immune cells may be associated with the progression of Alzheimer’s. 

Neutrophils are a type of immune cell that help heal damaged tissues and fight infections. The APOE gene is also found in the neutrophils. Preliminary studies from Dr. Rosenzweig’s team suggest that APOE-e4 may be associated with activating the inflammatory response of neutrophils in individuals with Alzheimer’s. However, how genetic variations of APOE found in neutrophils may interact with microglia to impact cognitive decline in individuals with Alzheimer’s is not yet fully understood.

Research Plan

Using genetically engineered Alzheimer’s-like mice, Dr. Rosenzweig and colleagues will study the impact of the genetic variations of APOE on the activity of neutrophils. In addition, the researchers will develop mouse models with genetically deleted APOE variations in mouse neutrophils. Dr. Rosenzweig’s team will then study the impact of neutrophil activity on the function of microglia in these mouse models. 

Further, the researchers will study the interaction between human neutrophils and microglia created from a special type of stem cell called induced pluripotent stem cells (iPSCs). iPSCs are stem cells engineered from adult human skin cells that can be reprogrammed into any type of cell, including microglia and neutrophils. Dr. Rosenzweig and colleagues will study the crosstalk between neutrophils- from individuals with different variations of the APOE gene- and microglia and study the impact of the crosstalk on brain changes observed in Alzheimer’s.

Impact

If successful, this project could provide a better understanding of how different immune cells interact with each other and how this crosstalk may impact brain changes observed in Alzheimer’s.