Sex differences in brain immune cells challenge research hypothesis

University of Rochester research reveals unexpected differences in how male and female brain immune cells respond to treatment, potentially impacting neurological disease research

Scientists have found that immune cells in the brains of men and women behave differently, a finding that could reshape how researchers approach neurological diseases that affect men and women.

The study, published in Cell Reports on January 21, 2025, challenges long-held assumptions about microglia, the brain’s resident immune cells, and their similarities between adult biological sexes. The team at the University of Rochester’s Del Monte Neuroscience Institute found that these cells responded very differently to certain treatments, depending on whether they were in male or female brains.

“This was a serendipitous discovery that had an impact on the work that people were doing in the field, but also helped us understand microglia biology in ways that people might not have thought of,” said Professor of Neuroscience and senior author of the study. said researcher Dr. Ania Majewska.

The discovery came as researchers studied how microglia respond to a drug called PLX3397, which is commonly used in laboratory settings to study the role of these cells in brain health and disease. . While male mice showed the expected response—the treatment depleted their microglia—female mice showed unexpected resilience, with their microglia adopting different survival strategies.

This sex-based difference helps explain why certain neurological diseases affect men and women differently. For example, Alzheimer’s disease is more common in women, while Parkinson’s disease is more common in men.

A research team led by first author Linh Le, Ph.D., found that female microglia respond to treatment by activating different cellular pathways than male microglia. These alternative strategies improve female microglia survival.

“These findings are critical to the rapidly emerging field of developing disease-modifying therapies that target microglia,” Majewska explained. She noted that researchers still don’t fully understand why microglia behave differently between the sexes, which is why microglia behave differently between the sexes. suggest that factors such as hormonal changes, inflammatory status, and baseline conditions may play an important role.

The implications extend beyond the laboratory. PLX3397 is currently used to treat certain rare joint tumors, and this study suggests its effects may differ between male and female patients. More broadly, the study highlights the importance of considering sex differences in research and treatment approaches to neurological diseases.

For the scientific community, these findings underscore the need to include both male and female subjects in studies—a practice that is not always standard. The discovery also opens new avenues for understanding how sex-specific differences in immune function affect brain health and disease progression.

The research team noted that future studies are needed to explore how these sex-based differences in microglial function influence the onset and progression of various neurological diseases. This could eventually lead to more targeted, gender-specific treatments for brain diseases.

This work was supported by multiple foundation grants from the National Institute of Neurological Disorders and Stroke, the Department of Defense, and the Del Monte Neuroscience Institute Pilot Program.