Researchers have discovered that the behavior of microglia differs between males and females, which could have significant consequences for the study of neurological diseases.
An incident occurs. Someone sustains an injury, perhaps a concussion. As emergency responders arrive to assist, a different group of responders within the brain is actively clearing away debris and repairing damaged tissues.
This group is known as microglia, the immune cells found in the central nervous system. Microglia are essential for preserving neuronal health by eliminating toxins from the brain and central nervous system. However, if they become overly active, they can harm neurons and may contribute to the advancement of neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
Sex-related differences in microglial function are recognized during development, yet it was previously believed that their activities were quite similar in adult males and females. Recent research from the Del Monte Institute for Neuroscience at the University of Rochester suggests that microglial behavior may not be as uniform between sexes as previously thought. This finding could significantly influence how diseases like Alzheimer’s and Parkinson’s are examined and emphasizes the need for gender-specific research. It is already established that Alzheimer’s affects more women while more men are diagnosed with Parkinson’s, but the reasons behind this disparity remain unclear.
“It’s an unexpected yet significant discovery that impacts ongoing work in the field and enhances our understanding of microglial biology,” explained Ania Majewska, PhD, a Neuroscience professor and senior author of a new study published in Cell Reports. The study illustrates how microglia react differently in adult male and female mice when an enzyme inhibitor is used to block their survival receptors. “This research broadens our knowledge regarding microglial biology, particularly in relation to diseases where these cells exhibit sex-specific importance.”
Pexidartinib, also known as PLX3397, is a widely used enzyme inhibitor in laboratory research to eliminate microglia, aiding scientists in investigating the role of these cells in brain health, function, and disease. Additionally, PLX3397 is utilized in treating the rare condition known as tenosynovial giant cell tumors (TGCT), which causes rapid growth of benign tumors in the joints.
While the Majewska Lab was utilizing PLX3397 for experiments involving male and female subjects, they faced challenges, prompting them to shift their focus to understanding the differential responses of microglia to the drug based on sex.
Linh Le, PhD (’24), a former graduate student in the Majewska Lab and first author of the study, observed the expected reaction in male microglia to PLX3397—blocking the receptor that signals their survival, leading to their depletion. However, Le and colleagues were surprised to discover that female microglia adopted a different signaling approach that resulted in enhanced survival and less depletion.
“These findings are pivotal in the swiftly advancing field of developing therapies that modify disease processes by targeting microglia,” noted Majewska. “We still do not fully understand why microglia behave differently between the sexes. Our goal is to comprehend how the signaling through this receptor is regulated under various conditions, such as hormonal fluctuations, basic states, or inflammatory responses.”
Additional contributors to the study include Sophia Eliseeva, Elizabeth Plunk, Kallam Kara-Pabani, Herman Li, and Felix Yarovinsky, PhD, from the University of Rochester. The research was funded by the National Institute of Neurological Disorders and Stroke, the Department of Defense, the Goodman Award, and the Kilian J. and Caroline F. Schmitt Foundation, through the Del Monte Institute for Neuroscience Pilot Program.
