Unveiling the Gender Gap: How Microglia Function Differently in Male and Female Brains

Summary: Microglia, the immune cells of the brain, are crucial for eliminating toxins and sustaining neuronal health; however, they can also exacerbate neurodegenerative disorders if excessively active. Recent studies uncover gender-based differences in the responses of adult male and female microglia to the enzyme inhibitor PLX3397, which is widely utilized in microglial research.

While male microglia exhibited the anticipated depletion, female microglia activated alternative signaling pathways, leading to enhanced survival. These results underscore the necessity for gender-specific studies in diseases such as Alzheimer’s and Parkinson’s, where microglial function is crucial and diagnosis rates vary by gender.

This advancement underscores the significance of customizing therapies targeting microglia according to gender. Further investigations aim to delve into hormonal and inflammatory factors impacting these disparities.

Key Facts:

• Gender-Based Microglial Differences: Male and female microglia react differently to PLX3397, with females demonstrating elevated survival.
• Neurodegenerative Consequences: These findings could alter the approach to developing and studying therapies for Alzheimer’s and Parkinson’s.
• Therapeutic Considerations: The activity of microglia that varies by gender may necessitate tailored treatment methodologies.

Source: University of Rochester

A collision occurs. An individual sustains an injury, a head trauma, a concussion. As the initial responders arrive to assist the individual, within the brain, another “team” of responders is engaged in removing debris and mending damaged tissue.

This team is referred to as microglia – the immune cells within the central nervous system. Microglia are essential for sustaining neuronal function by eliminating toxins from the brain and central nervous system.

Nonetheless, if overly active, they can harm neurons and, in some instances, have been associated with the advancement of neurodegenerative illnesses such as Alzheimer’s and Parkinson’s.

During developmental stages, there are recognized gender-related differences in microglial function. However, it was previously believed that variations in their behavior were minimal in adulthood. New research from the Del Monte Institute for Neuroscience at the University of Rochester indicates that microglial function may not be as uniform across genders as formerly assumed.

This revelation could have significant repercussions for the methodologies used to approach and investigate diseases like Alzheimer’s and Parkinson’s and highlights the imperative for gender-specific research. It is already established that Alzheimer’s diagnoses are more frequent in women, while Parkinson’s is diagnosed more in men; the reasons behind this remain unclear.

“This is a serendipitous discovery that has implications for ongoing work in the field and aids in understanding microglial biology in ways that were not anticipated,” stated Ania Majewska, PhD, professor of Neuroscience and the senior author of the study published today in Cell Reports that illustrates how microglia respond differently in adult males versus females when administered an enzyme inhibitor to obstruct their survival receptor.

This research bears far-reaching consequences for microglial biology and, consequently, all related diseases where microglia play a role in a gender-specific manner.

Pexidartinib, or PLX3397, is an enzyme inhibitor frequently used to deplete microglia in laboratory settings, assisting researchers in comprehending the role of these cells in brain health, function, and disease.

PLX3397 is also employed in treating the rare condition tenosynovial giant cell tumors (TGCT), which causes benign tumors to proliferate rapidly in the joints.

Researchers in the Majewska Lab were utilizing PLX3397 in experiments comparing males and females but faced challenges, prompting a shift in approach. Rather than using the inhibitor to pursue other inquiries, they decided to better comprehend how microglia responded to the drug in male and female subjects.

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 the study. They observed the expected response from microglia to PLX3397 in male mice—it obstructed the receptor that signals microglial survival, leading to reduced microglial count.

However, Le and colleagues were taken aback to discover that female microglia engaged a different signaling approach, resulting in improved survival and less depletion.

“These discoveries are pivotal in the swiftly evolving domain of developing disease-modifying therapies targeting microglia,” stated Majewska.

“We do not yet understand the reasons behind the divergent behaviors of microglia in the two sexes. We are eager to comprehend how the regulation of signaling through this receptor varies under different conditions, such as hormonal fluctuations, baseline states, inflammatory scenarios, or anti-inflammatory conditions.”

Additional contributors include Sophia Eliseeva, Elizabeth Plunk, Kallam Kara-Pabani, Herman Li, and Felix Yarovinsky, PhD, from the University of Rochester. This research received support from 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.

About this neuroscience research news

Author: Kelsie Smith Hayduk
Source: University of Rochester
Contact: Kelsie Smith Hayduk – University of Rochester
Image: The image is credited to Neuroscience News

Original Research: Open access.
“The microglial response to inhibition of Colony-stimulating-factor-1 receptor by PLX3397 differs by sex in adult mice” by Ania Majewska et al. Cell Reports

Abstract

The microglial response to inhibition of Colony-stimulating-factor-1 receptor by PLX3397 differs by sex in adult mice

Microglia, the resident macrophages of the brain, originate from the yolk sac and populate the brain prior to the establishment of the blood-brain barrier.

Once formed, they expand locally and depend on Colony-stimulating-factor-1 receptor (CSF1R) signaling for their growth and maintenance.

CSF1R inhibitors have been extensively used to deplete microglia in both healthy and diseased brain settings.

This study demonstrated gender-dependent differences in microglial responses to the CSF1R inhibitor PLX3397. Male mice displayed higher levels of microglial depletion compared to females.

Transcriptomic and flow cytometry analysis uncovered sex-specific differences in the remaining microglia population, with female microglia enhancing autophagy and proteostasis pathways while male microglia exhibited increased mitobiogenesis.

Moreover, modulating critical microglial receptors through various transgenic mouse lines led to variations in depletion efficacy that were also dependent on sex.

These findings indicate sex-dependent mechanisms of microglial survival, which may contribute to the well-acknowledged gender differences in multiple neurological disorders.