Rediscovering Microglia: Dr. Oleg Butovsky Discusses the Untapped Potential of Microglia in Neurodegenerative Diseases

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Oleg Butovsky, Ph.D., is an Assistant Professor of Neurology at Harvard Medical School. His laboratory at the Center of Neurologic Diseases in Brigham & Women’s Hospital focuses on the basic fundamental questions of microglia biology and developing novel microglia-targeting therapies. In addition, they are looking to develop novel tools and therapeutic approaches applicable to neurological diseases.

NS: How did you become interested in neuroimmunology?

OB: It’s my life! It’s not a job, it’s a calling, like being an artist. I studied microglia during my Ph.D. at the Weizmann Institute and felt it was a really amazing cell type. I’ve always believed we should do more to understand the biology of microglia and now that is what we have the opportunity to do.

NS: The field of neuroimmunology and neuroscience overall seems to be in a renaissance stage. What led to this renewed interest?

OB: It’s like the microglia is a new cell. Compared to how we have viewed microglia for the past twenty years it’s as though we discovered something completely novel. So we need to revisit everything we did before and reevaluate how we think of the origins and the function of microglia. Almost everything we thought we knew has been thrown out and we need to approach it with a fresh perspective.

NS: What would you say is the most interesting function of microglia? What is the least understood?

OB: We just don’t know what they do. The biology of the central nervous system (CNS) and the brain is so complex– the microglia interact with many different cell types in this environment. Our revelation came about five to six years ago when we discovered a TGF-b dependent, unique signature in microglia. We realized that microglia are very dynamic, highly reactive to their surroundings, and display multiple phenotypes. Therefore, they should have multiple functions. The big question is what phenotype corresponds to what function? Not just are the microglia good or bad, but also when are they good or bad? The data are highly contradictory but what we do know is that microglia can be important reflections of or even contributors to neurodegenerative disease. For example, we see that microglia are almost always involved in Alzheimer’s Disease (AD). All associated genes in AD are either highly or uniquely expressed in microglia. Microglia are obviously important cells but we just don’t have enough information yet about how they shape the immune response.

NS: What led you to begin working with NanoString?

OB: We started working with NanoString when we made a custom CodeSet to profile microglia. It has led to a lot of learning and collaborations for us. It is great technology that let us do quantitative, multiplexed gene expression in two to three days. We were able to do tough science in almost no time.

NS: Your lab is looking closely at the interplay between microglia and the peripheral immune response. What do you believe are the challenges and ultimately the benefits of this type of research?

OB: This question is the top priority in the study of microglial biology. When looking at microglia and recruited monocytes it is essential to know “who is who.” That’s why we developed unique markers to distinguish between resident and peripheral immune cells. They make different contributions to disease (either pathogenesis or recovery) and our goal is to understand that biology. One question we have is whether the recruited myeloid cells could take over the microglial function and substitute for the functioning microglial population. This would be an important advance for AD if we could replace the dystrophic microglia cells with healthy, functioning surrogates from the bloodstream.

NS: It has been said that unhealthy microglia are at the root of all neurodegenerative diseases. Your research also focuses on developing novel microglia-targeting therapies. What are some ways in which targeting the microglia can improve disease outcomes?

OB: A great advancement is that now we know the profile of microglia in healthy and disease states. Furthermore, we can categorize microglia into different subclasses within a disease. We have microglia specific to AD, to amyotrophic lateral sclerosis (ALS), and to stages within those diseases. We can define and refine phenotypes to gain more knowledge about what these cells do and how they function. To develop a therapy, we want to understand how we can alter the phenotype of a dysfunctional microglia to a healthy, functioning microglia. We are also looking at regulatory targets to manipulate the desired phenotype and induce a shift from homeostatic to neurogenic cells. We believe that if we can change the phenotype then we will change the course of the disease.

NS: Given the extreme plasticity of microglia cells do you believe their dysfunction will vary between neurodegenerative diseases?

OB: I think the microglia will be different throughout the spectrum of neurodegenerative diseases; how they vary remains to be seen. The common signature we described is a good starting point but it will be more interesting to look at the unique profiles of microglia per disease per stage. For example, ApoE is of interest in neurodegenerative disease because it has been the major regulator of the phenotypic switch from normal to disease-associated microglia. The specific phenotypes of microglia and the biomarkers they express are the most promising targets we can pursue.

NS: How do you believe NanoString’s Digital Spatial Profiling (DSP) Technology will be integrated into the Neuroscience field going forward?

OB: All the scientists in our center are intrigued by the ability to combine RNA and protein in a spatial manner. It’s a very cool technology and I think it will be giant. We need it and it will be used heavily. We will be able to look at more than just populations of cells; we’ll be able to look at their geography as well. We are very excited to start working with NanoString on this next chapter!

Learn more about how you can do “tough science in almost no time” with nCounter® Neuroinflammation Panels

View our webinar on the “Comprehensive analysis of microglia across neuropathological stages of Alzheimer’s disease (AD)” presented by Stefan Prokop, MD.

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