While neuroinflammation and oxidative stress resulting from the activity of innate immune cells in the central nervous system (CNS) are known to be associated with key neurodegenerative diseases including Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and Multiple Sclerosis (MS), until recently, important genetic characteristics of pathogenic immune cell populations were not well-defined.
By profiling the gene expression signature of oxidative stress-causing innate immune cells in a mouse model of Multiple Sclerosis, researchers from the Gladstone Institutes and the University of California San Francisco have shed light on the genetic mechanisms driving the behavior of these cells and discovered a compound that could reduce their damaging activity.
Their work involved the development of a novel method known as Tox-seq and could lead to data-driven approaches to treating neurodegenerative diseases.
“We were intrigued by our earlier findings that blood leaks in the brain activate innate immune cells to promote oxidative injury and neurodegeneration. Our motivation was twofold: identify the cell atlas of the oxidative stress innate immune cells and discover drugs to alleviate toxic effects of oxidative injury in the brain,” stated senior author of the study Katerina Akassoglou, PhD.
“We developed a new method called Tox-seq that integrates single-cell RNA-sequencing technology with selective labeling of cells that produce oxidative stress. This method reveals which genes are “on” or “off,” specifically in the cells that cause damage in the central nervous system. We combined this method with high-throughput screening of ~1,907 clinical drugs and bioactive compounds in microglia cells and pathway analysis.”
“We built a map that contains the gene signature of all immune cells that contribute to the buildup of toxic oxidative stress. We discovered a shared gene signature for oxidative stress between brain immune cells called microglia and infiltrating immune cells in the brain. This signature included coagulation, oxidative stress, and glutathione-pathway genes.”
“Microglia high-throughput screen identified the compound acivicin, which targets the glutathione degrading enzyme GGT. Acivicin showed potent therapeutic effects that decreased oxidative stress and neurodegeneration in multiple sclerosis animal models.”
“A key contribution is the discovery of a core oxidative gene signature for the innate immune cells in the brain that drastically changes our understanding how neuroinflammatory disease develops and progresses, as well as how it can be treated,” Dr. Akassoglou continued.
The study, “Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation,” was published in the journal Nature Immunology. Moving forwards, the team plans to focus on investigating immune cell activity at or near blood vessels in the brain in MS and AD.
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“Our future research focuses on the discovery of new mechanisms at the blood-brain-immune interface in neurological diseases. The neurovascular interface is a rich niche for the discovery of new tools to diagnose and treat neurological diseases.”
Dr. Akassoglou’s take-home message: “Targeting the vicious cycle between toxic innate immune cells and blood coagulation is a new frontier to combat neurodegeneration.”