New findings challenge long-standing assumptions about microglia; the brain’s resident immune cells, highlighting significant sex-specific differences that could reshape research into neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
A study conducted by the Del Monte Institute for Neuroscience at the University of Rochester examined how microglia in adult male and female mice responded to a commonly used enzyme inhibitor, PLX3397, which blocks the Colony-Stimulating Factor 1 Receptor (CSF1R) essential for microglia survival. The results, published in Cell Reports, reveal that male microglia were more susceptible to depletion by the drug, while female microglia activated pathways that enhanced their survival.
Microglia serve critical roles in brain health, from clearing toxins to maintaining neuronal function. However, their overactivity can contribute to neurodegenerative diseases. These findings underscore the need to investigate how sex-specific differences in microglial behavior influence the onset and progression of conditions like Alzheimer’s and Parkinson’s, which disproportionately affect women and men, respectively.
“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,”
stated Anna Majewska, PhD, professor of neuroscience at the University of Rochester and senior author of the study.
“Microglia, the resident macrophages of the brain, are derived from the yolk sac and colonize the brain before the blood-brain barrier forms. Once established, they expand locally and require Colony-stimulating-factor-1 receptor (CSF1R) signaling for their development and maintenance. CSF1R inhibitors have been used extensively to deplete microglia in the healthy and diseased brain,”
The research team used PLX3397 to inhibit CSF1R, observing that male mice exhibited greater microglial depletion compared to females. Transcriptomic and flow cytometry analyses revealed that female microglia activated autophagy and proteostasis pathways to sustain survival, while male microglia upregulated mitobiogenesis. These sex-dependent responses suggest that microglial survival mechanisms differ fundamentally between males and females.
Experiments using mice with genetically modified microglial receptors tested these findings again further reinforcing them. The results show why medical treatment for microglia must consider sex differences when developing therapies for patients.
The research reveals unexplored details about how sex and biological factors affect brain immunity through hormones and inflammation, and basal metabolic states. Scientists expect the discovery of these pathways will help them create better treatments for neurodegenerative conditions.
“This work highlights the importance of considering sex as a biological variable in neuroscience research,”
said Linh Le, first author of the study and now a research scientist at SetPoint Medical. Linh Le went on to say:
“As we move towards disease-modifying therapies targeting microglia, this knowledge will be instrumental in improving treatment outcomes.”
Studies show scientists should investigate the brain using methods that include both male and female subjects. Study results show how male-led neuroscience methods fail to recognise important variations in brain characteristics. The study reveals biological differences between females and males that researchers can explore to help create better neurological disorder treatment methods.
Researchers must build better scientific tools and brain modelling methods that honour gender differences to progress effectively in fighting brain-related illnesses.
