When most people think of the brain, we primarily imagine neurons. Neurons are the cells that use electrochemical signaling to directly control our thoughts, actions, and memories. However, neurons are not the only type of cell in the brain. Microglia are a type of immune cell that protects the brain against infections or injuries, among other important roles. One particularly important function of microglia is that they help to clear away amyloid-beta, a toxic protein that is believed to cause Alzheimer’s disease when it accumulates in the brain.
A group of researchers from the University of Pennsylvania wanted to learn more about the role microglia play in Alzheimer’s disease. Their work was published in the journal Acta Neuropathologica.
The researchers used a fairly new technique called single-nuclei RNA sequencing (snRNA-seq), which can reveal what genes are expressed in individual cells. They analyzed cells from the brains of deceased human Alzheimer’s disease patients. By analyzing their gene expression, they were able to categorize the microglia into four distinct groups. One of these groups, called amyloid-responsive microglia, may be important for avoiding Alzheimer’s disease by keeping toxic amyloid-beta at bay.
Next, the researchers wanted to focus on two particular genes called APOE and TREM2. Both of these genes may be involved in regulating how microglia respond to amyloid-beta. Previous studies have shown that genetic variants in APOE and TREM2 can influence the risk of developing Alzheimer’s disease.
The researchers looked at the brains of people who had versions of APOE and TREM2 that are associated with a higher risk of Alzheimer’s disease. These versions are known as risk variants. They found that individuals with risk variants in these two genes had fewer numbers of amyloid-responsive microglia in their brains. This result is exciting, as it provides a potential mechanism for how these genes influence the risk of Alzheimer’s via changing a particular category of microglia.
“These findings demonstrate that not all microglia respond the same to protein that builds up, or aggregates, in the brain,” says Dr. Aivi Nguyen, a former neuropathology and post-doctoral fellow who was the lead author on the paper. “Moreover, certain genetic risk factors are associated with specific types of microglial responses. Thus, neuroinflammation, or microglia getting revved up, may not be as binary as “good” or “bad.” Perhaps the answer is simply: it depends.”
Dr. Nguyen says she first became interested in this topic due to having a family member with Parkinson’s disease. “I did not realize how much I would enjoy the field, though,” she added. She also commented on the importance of a positive lab culture for her scientific success. “I have found this community to be incredibly supportive and encouraging, particularly as a woman neuropathologist. An example of this positive culture is my mentor, Dr. Eddie Lee, who has helped me enormously and has advocated on my behalf on countless occasions.”
Dr. Nguyen and her coauthors plan to follow up on this study by investigating amyloid-responsive microglia in more detail. Their research could offer new insights into the role microglia play in Alzheimer’s disease and whether they could be a target for future therapeutics.