Summary: Microglia, the brain’s immune cells, play an essential role in eliminating toxins and maintaining neuronal health, but can also contribute to neurodegenerative diseases when hyperactive. New research reveals sex-based differences in how adult male and female microglia respond to the enzyme inhibitor PLX3397, a common tool in microglial research.
While male microglia exhibited the expected exhaustion, female microglia used alternative signaling pathways, leading to increased survival. These findings highlight the need for sex-specific research in diseases such as Alzheimer’s disease and Parkinson’s disease, where microglial activity plays an important role and diagnosis rates differ by sex.
This advance highlights the importance of tailoring therapies targeting microglia based on gender. Further research aims to explore the hormonal and inflammatory factors influencing these differences.
Key facts:
- Microglial differences based on sex: Male and female microglia respond differently to PLX3397, with females showing increased survival.
- Neurodegenerative impact: The findings could reshape the way Alzheimer’s and Parkinson’s therapies are developed and studied.
- Therapeutic implications: Sex-specific microglial activity may require tailored treatment strategies.
Source: University of Rochester
A collision occurs. Someone gets hurt, head trauma, concussion. Just as first responders arrive to help the person, inside the brain, another “team” of responders is busy clearing debris and repairing injured tissue.
This crew is called microglia – the immune cells of the central nervous system. Microglia are essential for maintaining neuronal function by removing toxins from the brain and central nervous system.
But if they are overactive, they can damage neurons and, in some cases, promote the progression of neurodegenerative diseases like Alzheimer’s and Parkinson’s.
During development, there are known sex differences in microglial function. But as adults, there was thought to be less variation in their behavior. New research from the Del Monte Institute for Neuroscience at the University of Rochester reveals that microglia function may not be as similar across sexes as once thought.
This finding could have broad implications for how diseases like Alzheimer’s and Parkinson’s are approached and studied, and highlights the need for gender-specific research. We already know that more women are diagnosed with Alzheimer’s disease and more men are diagnosed with Parkinson’s disease, but we don’t know why.
“This is an incidental finding that has implications for what people in the field do, but also helps us understand the biology of microglia in ways that people may not have expected,” said Ania Majewska, PhD, professor of neuroscience and lead author. from a study published today in Cell Reports This shows how microglia respond differently in adult male and female mice when given an enzyme inhibitor to block its microglia survival receptor. “
This research has many ramifications for microglia biology and, therefore, for all those diseases in which microglia are important in a sex-specific manner.
Pexidartinib or PLX3397 is an enzyme inhibitor commonly used to eliminate microglia in the laboratory 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 cell tumors (TGCT), a disease that causes benign tumors to grow rapidly in the joints.
Researchers at the Majewska lab were using PLX3397 in male versus female experiments, but continued to encounter difficulties. So they decided to take a different approach with the inhibitor. Instead of using it to ask further questions, they decided to better understand how microglia responded to the drug in men compared to women.
Linh Le, PhD (’24), currently a research scientist at SetPoint Medical Corp, was a graduate student in the Majewska lab and is the first author of this study, discovered the expected response of microglia to PLX3397 in male mice: she blocked the receptor that signals microglia survival and depletes microglia.
However, Le et al. were surprised to find that female microglia responded with a different signaling strategy, resulting in increased microglial survival and decreased exhaustion.
“These results are crucial in the emerging field of developing disease-modifying therapies targeting microglia,” Majewska said.
“We don’t yet know why microglia act differently in the two sexes. I think we would like to understand how signaling through this receptor is regulated under different conditions, i.e. hormonal changes, a basal state, an inflammatory state or an anti-inflammatory state.
Other authors include Sophia Eliseeva, Elizabeth Plunk, Kallam Kara-Pabani, Herman Li, Felix Yarovinsky, PhD, of the University of Rochester. This work was supported 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 Institute Pilot Program Go up for neuroscience.
About this neuroscience research news
Author: Kelsie Smith Hayduk
Source: University of Rochester
Contact: Kelsie Smith Hayduk – University of Rochester
Picture: Image is credited to Neuroscience News
Original research: Free access.
“Microglial response to colony-stimulating factor 1 receptor inhibition by PLX3397 differs by sex in adult mice” by Ania Majewska et al. Cell Reports
Abstract
Microglial response to colony-stimulating factor 1 receptor inhibition by PLX3397 differs by sex in adult mice
Microglia, the resident macrophages of the brain, derive from the yolk sac and colonize the brain before the formation of the blood-brain barrier.
Once established, they grow locally and require CSF1R (Colony-stimulating-factor-1) receptor signaling for their development and maintenance.
CSF1R inhibitors have been widely used to deplete microglia in healthy and diseased brains.
In this study, we demonstrated sex differences in the microglial response to the CSF1R inhibitor, PLX3397. Male mice had greater microglial depletion than females.
Transcriptomic and flow cytometry analysis revealed sex-specific differences in the remaining microglia population, with female microglia positively regulating autophagy and proteostasis pathways, while male microglia increased mitobiogenesis.
Furthermore, manipulation of key microglial receptors using different transgenic mouse lines resulted in changes in depletion efficiency that were also sex dependent.
These findings suggest sex-dependent microglial survival mechanisms, which may contribute to the well-documented sex differences in various neurological disorders.
