2025 AD Strategic Fund: APOE Biology in Alzheimer's (ABA) (ABA)

APOE variant impact on amyloid-b phagosome composition of human microglia

How do gene variations linked to Alzheimer’s impact immune cells behavior?

Helen Goodridge, PhD, & David Underhill, PhD
Cedars-Sinai Medical Center
Los Angeles, CA - United States

Background

Genes play an important role in Alzheimer’s. The apolipoprotein E (APOE) gene provides instructions for making ApoE protein. There are several genetic variations of APOE, including APOE-e2, APOE-e3 and APOE-e4. In some populations, the APOE-e4 variation is thought to increase a person’s risk of developing Alzheimer’s, whereas APOE-e2 may decrease a person’s risk. APOE-e3 seems to have no impact on Alzheimer’s risk.

The brain’s primary immune cells are called microglia. Microglia play a major role in helping to maintain healthy nerve cells in the brain. Individuals with Alzheimer’s typically experience brain inflammation caused by changes in the immune system, including increased activity of microglia. When microglia encounter dead cells, microbes, or other particles, they react by swallowing them; this process is called phagocytosis. Inside of microglia, the structures containing the swallowed pieces are called phagosomes. 

Early brain changes in Alzheimer’s disease include buildup of a protein called beta-amyloid. Microglia will swallow beta-amyloid, and phagosomes can reveal how well the cells are processing these clumps of beta-amyloid. In preliminary research, Drs. Helen Goodridge, David Underhill and colleagues developed a method to catalog the contents of phagosomes. They will use this approach to study beta- amyloid processing by phagosomes in microglia.

Research Plan

Dr. Goodridge, Dr. Underhill and colleagues will use a specialized type of stem cell called induced pluripotent stem cells (iPSCs). These are adult human skin cells that can be “reprogrammed” into any type of cell in the body, including microglia, and grown in laboratory dishes. They will study how in healthy microglia and in microglia engineered to include different APOE variations, the beta-amyloid is processed by the phagosomes. In doing these experiments, they hope to identify proteins that may regulate amyloid beta processing and brain inflammation.

Impact

Results of this study could improve our understanding of how APOE and the immune system may interact with one another in Alzheimer’s to impact a person’s disease and progression. It may also identify new potential targets for therapeutics.