09/25/2024
Cleveland Clinic researchers receive $3.9 million to explain how oxidative stress affects microglia in Alzheimer’s disease
Cleveland Clinic neuroscience researchers Tatiana Byzova, PhD, and Eugene Podrez, MD, PhD, are leading a $3.9 million project to detail how oxidative stress connects to microglial dysfunction, inflammation and, potentially, Alzheimer’s disease.
The project, supported by the National Institute on Aging, aims to understand the chemistry behind a vicious cycle of inflammation and cell dysregulation that contributes to Alzheimer’s disease. Drs. Podrez and Byzova will also investigate a new strategy for stabilizing the cells causing pervasive and damaging inflammation.
Oxidative stress is an imbalance of molecules in the brain that can cause inflammation and cell damage and is tied to neurodegenerative disease. In their previous work, Drs. Byzova and Podrez found that oxidization of fats in the brain (PUFAs) produced molecules called novel membrane-bound Reactive Core Aldehydes (RCAs). The brain is the most sensitive tissue for RCA-induced damage, Dr. Podrez explains. The team has developed a method to detect all proteins modified by RCAs within the brain, he says, allowing for unprecedented investigation into Alzheimer’s disease and other neurodegenerative conditions.
This project aims to clarify further how RCAs affect the function of microglia using these targets – brain cells that ideally protect the brain and clean up injuries, but also are linked to inflammation that causes Alzheimer’s disease.
“Almost all neurodegenerative diseases start with microglial dysfunction,” Dr. Byzova says. “Through our analysis, we’ve built a map of human RCA pathway targets; people knew some of these targets were connected to Alzheimer’s disease, but they didn’t previously know how.”
Defining this pathway also helps explain sex-based differences in Alzheimer’s disease. Almost two-thirds of diagnoses in the U.S. are in women, according to the Alzheimer’s Association. By investigating interactions that occur with targets specific to women, future findings could shape sex-specific therapeutic discovery, Dr. Byzova says.
The research team took a unique approach to defining these targets. Current preclinical models are limited. Instead, the research started with brain tissue samples obtained through the National Disease Research Interchange. The team was able to build a library of samples, gather initial data and test initial hypotheses.
How do microglia become dysregulated?
Microglia typically stick to their own areas of the brain, cleaning up injuries and debris. During this repair process, the cells signal to the immune system for help, which causes inflammation. This is protective at certain levels but can build up if the process becomes dysregulated.
Previous studies showed that when certain proteins are modified or “knocked out” in microglia, the cells clump up instead of staying to their own areas. This interferes with their role in managing injury and causes a feedback loop where more inflammation occurs. Researchers have found microglia clumped around the brain plaques that are hallmarks of Alzheimer’s disease.
Dr. Byzova, staff in Neurosciences, and Dr. Podrez, staff in Inflammation & Immunity, plan to look at how microglia may become dysregulated through the RCA pathway, with a focus on the role of the protein kindlin3. Knocking out kindlin3 has been shown to negatively affect the microglial membrane, interfering with its functions and causing inflammation.
How do researchers propose reducing the inflammatory effects of oxidative stress?
The research team plans to test a “RCA sponge,” which is a drug designed to combat the RCA molecules. The compound is designed to reduce oxidization and prevent the cell membrane from being altered.
Watching how this compound affects microglia and inflammation in preclinical work will provide more insight into how these pieces are connected and whether this could serve as a potential therapeutic strategy for patients.
