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Sex Differences in Brain Immune Cells Challenge Research Assumptions

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

Scientists have discovered that the brain’s immune cells behave differently in males and females, a finding that could reshape how researchers approach neurological diseases that affect men and women at different rates.

The research, published in Cell Reports on January 21, 2025, challenges long-held assumptions about microglia – the brain’s resident immune cells – and their similarity across biological sexes in adults. The team at the University of Rochester’s Del Monte Institute for Neuroscience found that these cells respond quite differently to certain treatments depending on whether they’re in male or female brains.

“It is a fortuitous finding that has repercussions for what people are doing in the field, but also helps us understand microglia biology in a way that people may not have been expecting,” says Ania Majewska, PhD, professor of Neuroscience and the study’s senior author.

The discovery emerged when researchers were studying how microglia respond to a drug called PLX3397, commonly used in laboratory settings to study these cells’ roles in brain health and disease. While male mice showed the expected response – the treatment depleted their microglia – female mice demonstrated unexpected resilience, with their microglia employing different survival strategies.

This sex-based variation could help explain why certain neurological conditions affect men and women differently. For instance, Alzheimer’s disease is diagnosed more frequently in women, while Parkinson’s disease is more common in men.

The research team, led by first author Linh Le, PhD, found that female microglia responded to the treatment by activating different cellular pathways than their male counterparts. These alternative strategies resulted in increased survival rates among female microglia.

“These findings are crucial in the rapidly emerging field of developing disease-modifying therapies that target microglia,” Majewska explains. She notes that researchers still don’t fully understand why microglia behave differently between sexes, suggesting that factors such as hormonal changes, inflammatory states, and baseline conditions might play important roles.

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

For the scientific community, these findings underscore the necessity of including both male and female subjects in research – a practice that hasn’t always been standard. The discovery also opens new avenues for understanding how sex-specific differences in immune function might influence brain health and disease progression.

The research team notes that future studies will need to explore how these sex-based differences in microglia function might influence the development and progression of various neurological conditions. This could eventually lead to more targeted, sex-specific treatments for brain diseases.

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


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