Microglia are the first line of immune defense in the central nervous system, particularly in the brain. With roughly 10–15 percent of brain cells being microglia (1), researchers were keen to establish how these cells sometimes begin to show toxicity and start to work against our body’s immune system.
A new study published in Nature has established that some of this toxic transformation is spurred on by blood entering the brain, which activates genes linked with the development of diseases in the brain and central nervous system (2).
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“Epidemiological evidence shows that blood leaks in the brain correlate with early disease onset and worse prognosis in neurological diseases,” says Katerina Akassoglou, a co-author on the paper. “I was intrigued by the gap in knowledge of whether blood proteins are drivers of pathogenic processes in the brain that can instigate diseases like multiple sclerosis or Alzheimer’s disease.”
The study showed that specific proteins that enter the brain through a disruption to the normal blood–brain barrier are able to hijack receptors in the microglia to elicit toxic effects on neurons. “We found that the blood protein fibrinogen – which normally aids blood clotting – is responsible for turning on harmful genes in microglia.”
One interesting finding, according to Akassoglou, was the specificity that the blood proteins had on influencing the pathogenesis of brain disease – as well as the sheer number of responses that blood proteins can elicit in microglia. “I was surprised by the large number of shared neurotoxic gene pathways between multiple sclerosis and Alzheimer’s disease,” she says. “This finding could be important for developing therapies to target neurotoxic immune populations across neurodegenerative diseases.”
The research in the study was made possible by recent developments in multiomic profiling techniques – specifically, RNA sequencing and mass spectrometry. The methodology – used for the first time in this way for the study – allowed the team to investigate the global expression of genes and proteins in cells and how they react to a stimulus, rather than focusing on individual genes and proteins.
The findings have implications beyond therapies, says Akassoglou. “[They] can also support the development of fluid and imaging biomarkers for neurological diseases. Blood leaks in the brain are early events that precede brain inflammation, and they correlate with worse prognosis for neurological diseases… These proteins can be further studied for their potential as biomarkers detected in body fluids or as targets for developing new imaging probes.”
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References
- SE Dos Santos et al., “Similar Microglial Cell Densities across Brain Structures and Mammalian Species: Implications for Brain Tissue Function,” J Neurosci, 10, 4622 (2020). PMID: 32253358.
- AS Mendiola et al., “Defining blood-induced microglia functions in neurodegeneration through multiomic profiling,” Nat Immunol (2023). PMID: 37291385.
