Postdocs discuss neurodegenerative conditions for 'Scientifically Speaking'

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The Jackson Laboratory's "Scientifically Speaking" virtual series continues May 7, featuring two postdoctoral associates taking on the challenge of neurodegenerative disease.

Ashley Gardner, Ph.D., and Michael Maclean, Ph.D., are using genetics to find solutions to neurodegenerative conditions such as Alzheimer's disease, dementias, multiple sclerosis and diabetic retinopathy, one of the world's leading causes of vision loss. We sat down with Gardner and Maclean to find out about their research and hopes for the future of these complex diseases.

Ashley Gardner is a postdoctoral associate in the laboratory of Lenny Shultz, Ph.D., where she is working to create models that better mimic what happens in a human brain during neurodegenerative and neuroinflammatory disease, so that her findings will be relevant in a clinical setting.

The Jackson Laboratory's Ashley Gardner. Photo credit: Tiffany Laufer.

Q. Break down the term "neuroimmunology." What does it mean?

A. In this context, "neuro" refers to the brain, and "immunology" is the study of the immune system. The same system that protects you from bacteria and viruses actually plays a big role in your brain function and protection. For many decades, scientists thought the healthy brain was an "immune-privileged site," meaning that immune cells were not present and did not contribute to the brain's daily activities. We now understand that, while the brain has a natural barrier that makes it a unique cellular environment, there are, in fact, immune cells that regularly cross that barrier. Some immune cells even live in the brain permanently. Neuroimmunology refers to the study of these cells and how they react when the brain is threatened.

I study a type of cell known as microglia, often called the "resident immune cell" of the brain. These cells are constantly patrolling the brain for damage and will protect it from pathogens, cancer, toxins or cell damage. If they identify something as harmful, microglia start attacking it and eating up the debris. There is a flip side to this if these cells become hyperactive. They become harmful by killing off healthy cells as well as damaged ones. We need microglia for our neurological health, but they need to be doing just the right amount of work.

Q. What do you find most meaningful about your research?

A. When I tell people about my focus on neurodegenerative disease, almost everyone says they have a family member, friend or loved one suffering from dementia. Some of the people I meet are curious about the science, but many are just grateful that there are people working in this area. And my research relates to a range of health challenges, such as stroke, traumatic brain injury and aging. As a first responder, I have met patients affected by these conditions, so I also find a lot of meaning in the potential impacts of my research on patients and their loved ones.

What drew me to Lenny Shultz's lab in particular was the work he's doing to close the gap between mouse research and human disease. We study humanized mouse models, meaning we put human cells into a mouse to study how the human cells behave. We're able to study the actions of these cells and manipulate variables in a way that simply isn't possible with human patients. We can also use humanized mice to test how human cells respond to potential new therapeutics before they go to clinical trials.

Q. What kinds of projects are you working on in your lab?

A. Our team is working on growing human microglia, those protective immune cells that reside in the brain, in a mouse brain. We inject human cells into the brains of newborn mice, which then travel into the brain, take up the brain environment, and grow into human microglia for us to study. So far, we have successfully done this through two different methods. Both resulted in human microglia development in the mice, yet the microglia looked different depending on the method. It was almost the equivalent to wearing two different uniforms: one method resulted in the microglia wearing an apron and a chef's hat, and the other method resulted in microglia wearing a pilot's uniform. That's interesting simply because we now want to figure out why. It opens up a whole new area of potential research.

We're now working to put these human cells into a mouse brain that does not have any microglia of its own through a genetic intervention that our team developed. This creates a "clean slate" for the human microglia that arrive, and I'm so fascinated to see if that is going to work the way we think it will.

The eye-brain connection

The Jackson Laboratory's Michael Maclean. Photo credit: Tiffany Laufer.

Michael MacLean works in the Howell lab, where he has been studying Alzheimer's disease and metabolic syndrome. Metabolic syndrome encompasses conditions like obesity, diabetes and hypertension that influence a person's likelihood of developing neurodegenerative conditions, including Alzheimer's disease and diabetic retinopathy. He wants to find out how those factors influence the immune cells in the brain and the eye, and how they might promote neurodegeneration.

Q. Tell us more about the discoveries you'd made in researching diabetic retinopathy.

A. We're trying to target the immune cells of the central nervous system in disease models of diabetic retinopathy and Alzheimer's disease to see if we can alleviate the pathology. I'm working on Alzheimer's disease in a model of metabolic syndrome with many of the same metabolic impairments observed in humans. I wondered if these mice also developed degeneration in the eye. This model has been in circulation at JAX for 30 years, but this is the first time we've thought to examine their eyes for signs of retinal degeneration. We think it's a better model for diabetic retinopathy than any we've seen before.

The current treatments for retinopathy are not perfect. All involve injections or lasers in the eye, which can be scary for patients. And once you're diagnosed with diabetes, you're very likely to develop some degree of retinopathy over time. It's one of the largest causes of vision loss worldwide. If we can target new mechanisms of neurodegeneration, it could potentially lead to more effective, less invasive treatments.

Q. How do you hope this new model will make a difference in advancing research around eye-related conditions?

We've been able to non-invasively track the eye health of this model for about a year. Now, we want to test different therapeutics in a way that could be translated to the clinic more readily. There's a lot of opportunity for discovery and validation of candidate drugs that have been suggested in the literature about diabetic retinopathy. We'll be able to test quite a few, and I'm excited to see what we learn.

The myriad of conditions that underlie metabolic syndrome - hypertension, diabetes, obesity, etc. - put us at risk for many other health challenges. So it's crucial to understand how these common conditions influence the immune cells within the brain and retina and if shared mechanisms drive common neurodegenerative diseases such as Alzheimer's disease and diabetic retinopathy. The data resources and mouse models we generate throughout these projects are publicly available for anyone who wants to collaborate or further the research on their own.

Q. What makes JAX the right place for you to advance this research?

A. This is an easy one to answer. JAX has a huge number of mouse models that are unique for many different reasons, which means they can be studied in different ways. In the Howell lab, for example, we just finished a study where we observed nine different types of mice across different ages to understand how aging influences the retina. We wanted to find out not only how aging affects one mouse, which might be unique in the way a person is unique, but also how it influences a broader genetically diverse population that mirrors the diversity of the human population. Our main question was, how does age affect the retina, and does that dictate who might be more susceptible to developing a neurodegenerative disease of the eye? These insights will likely be applicable to the aging brain as these tissues share many similarities.

Once we know these answers, we can identify new models, test a therapeutic in a different way, or identify new pathways that could be a good target for therapeutic engagement for reducing aging effects in the eye. Other institutions simply don't have the diversity of resources. We could only do this kind of work at JAX.

Learn more about how you can help support solutions for Alzheimer's disease, dementia and other neurodegenerative conditions by visiting www.jax.org/give.

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