NIH support from: NINDS, NIMH, NIGMS, NCATS
New research from the University of Rochester finds that microglia function may not be as similar across sex as once thought. This discovery could have broad implications for how diseases like Alzheimer’s and Parkinson’s are approached and studied, and points to the necessity of having gender-specific research. It is already known that more women are diagnosed with Alzheimer’s and more men are diagnosed with Parkinson’s, but it’s unclear why.
Microglia are the immune cells of the central nervous system, clearing toxins in the brain. But if they are overactive, they can damage neurons instead and, in some cases, have been found to promote the progression of neurodegenerative diseases like Alzheimer’s and Parkinson’s. Although there are known sex-related differences in how microglia function, it was thought to be less variation in how they behave in adulthood. The new study showied how microglia respond differently in adult male versus female mice when given an enzyme inhibitor to block its microglia survival receptor.
“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,” said Ania Majewska, PhD, professor of Neuroscience and senior author of the study in Cell Reports. “This research has a lot of ramifications for microglia biology and as a result all these diseases where microglia are important in a sex-specific manner.”
Pexidartinib or PLX3397 is an enzyme inhibitor commonly used to remove microglia in the lab setting to help researchers better understand the role of these cells in brain health, function, and disease. PLX3397 is also used to treat the rare disease tenosynovial giant cells tumours (TGCT), a condition that causes benign tumours to grow rapidly in the joints.
Researchers in the Majewska Lab were using PLX3397 in male versus female experiments but continued to run into difficulties, so they decided to take a different approach with the inhibitor. Instead of using it to ask other questions, they decided to better understand how microglia were responding to the drug in males versus females.
First author Linh Le, PhD (‘24), currently a Research Scientist, SetPoint Medical Corp, was a graduate student in the Majewska Lab when she found the expected response from microglia to PLX3397 in male mice: it blocked the receptor that signals microglial survival and depleted the microglia. However, Le, et al, were surprised to find that female microglia responded with a different signalling strategy that resulted in increased microglial survival and less depletion.
“These findings are crucial in the rapidly emerging field of developing disease-modifying therapies that target microglia,” said Majewska. “We do not yet know why the microglia are acting differently in the two sexes. I think we’d like to understand how the signaling through this receptor is regulated in different conditions, such as hormonal changes, basal state, inflammatory, or an anti-inflammatory state.”
