Researchers have long noted sex-related differences in the function of microglia, the immune cells present in the central nervous system that play an important role in neurological function. Previously, these differences were thought to occur mainly during development, with more uniform functions occurring during adulthood. However, recent research from the Del Monte Institute for Neuroscience at the University of Rochester suggests notable sex-based microglial differences into adulthood. The findings, which were published in the journal Cell Reports, could have broad implications for the scientific community’s understanding of microglia. The findings could also broaden the understanding of microglial impact on neurodegenerative diseases like Alzheimer’s disease (AD) and Parkinson’s disease (PD), potentially paving the way for more highly targeted, sex-specific treatment options.
Sex-Based Differences in Microglia Behavior
Microglia are located throughout the central nervous system; they’re found in the brain, spinal cord, and retina. These immune cells play an important role in neuronal function, working to clear toxins throughout the brain and central nervous system. However, overactive microglia can damage properly functioning neurons, potentially promoting the progression of neurodegenerative diseases. Some elements of microglial behavior remain a mystery, but researchers know that these essential immune cells can become overactive due to a variety of factors. Those factors might include brain injury, infection, accumulation of damaged proteins, chronic stress, and aging.
The Del Monte Institute team based their research on a question: Do microglia respond differently in adult male versus female mice when the mouse models are given an enzyme inhibitor to block their microglia survival receptors? Beyond that, could any sex-based differences observed during research be applied to noted sex-based differences in neurodegenerative diseases — for example, the fact that more women are diagnosed with AD and more men are diagnosed with PD? To find out, the team deployed a well-known enzyme inhibitor.
Using Enzyme Inhibitors to Remove Microglia
To explore sex-based microglia behavior, the team used pexidartinib, or PLX3397, an enzyme inhibitor commonly used to remove microglia in a lab setting. Unsurprisingly, when the team applied PLX3398 to male mice, it blocked the receptor that signals microglial survival, depleting the immune cells. However, when the team applied the same technique to female mice, they witnessed something surprising: The female microglia exhibited a different signaling strategy, which resulted in increased microglial survival overall.
Why did the microglia act differently in male mice and female mice? The team isn’t sure yet. Researcher Linh Le, Ph.D., noted that the researchers still need to explore how “signaling through this receptor is regulated in different conditions, i.e. hormonal changes, basal state, inflammatory, or an anti-inflammatory state.” However, this noted sex-based difference could be significant, especially when tailoring treatment for individual patients with neurodegenerative diseases hallmarked by overactive microglia.
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While further research is needed, these new insights could prove valuable when studying neurodegenerative diseases like AD and PD. “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,” wrote Ania Majewska, Ph.D., the senior author of the study.
To study microglia, Scantox Neuro offers several different in vitro and in vivo models of neurodegenerative diseases, such as AD, PD, ALS. Furthermore, specific in vitro and in vivo models of neuroinflammation are available. Tissue of these models can be evaluated biochemically and histologically for microglia-specific biomarkers.
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