Selective Blockade of Mitochondrial Free Radicals in AD
Aging and neurodegenerative disease are associated with the accumulation of free radicals (also called oxidative stress) in the brain and other organs. Oxidative stress can damage cells and organs, promote disease, and impair brain function. We recently discovered small molecules that can block specific causes of oxidative stress without affecting normal cell functions. Our proposed studies will test whether these small molecules have therapeutic benefits in experimental models of dementia.
Our goal is to determine whether blocking specific origins of oxidative stress is a promising therapeutic approach for AD, FTD, and related dementias. In this project, we will test whether stopping the production of free radicals that lead to oxidative stress and brain damage can slow or prevent neurodegenerative disease. We will use newly discovered and highly selective blockers of free radicals that we predict will have multipronged benefits on neuronal and glial function in experimental models of disease. If successful, these studies would provide the first evidence that this approach is effective for reducing brain damage and inflammation, and might be effective for treating a variety of neurodegenerative disorders. These findings would open an exciting new frontier in the fight against dementia and greatly advance clinical testing and development of new treatments.
About the Researcher
Dr. Anna Orr is an Assistant Professor of Neuroscience at the Helen and Robert Appel Alzheimer’s Disease Research Institute and the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine. She earned a Bachelor's degree in Neuroscience and Psychology from Allegheny College and Ph.D. in Neuroscience from Emory University, where she worked with Dr. Stephen Traynelis on mechanisms of glial motility, glial responses to brain injury, and receptor signaling in brain inflammation. Dr. Orr completed postdoctoral training with the guidance of Dr. Lennart Mucke at the Gladstone Institute of Neurological Disease and UCSF. At Gladstone, Dr. Orr led studies demonstrating that receptor signaling in astroglia regulates long-term memory and can contribute to memory loss in disease. Her graduate and postdoctoral training was supported by two NIH fellowships and pilot funding from the UCSF Alzheimer’s Disease Research Center. Dr. Orr’s laboratory at Weill Cornell Medicine focuses on glial-neuronal interactions and mitochondrial signaling in normal and pathophysiological processes. The lab investigates how receptors and proteins linked to neurodegenerative disease affect glial cells and glial-neuronal interactions that are critical for normal brain function. In partnership with Dr. Adam Orr, who is a co-investigator and key contributor, the team is also investigating how mitochondrial production of reactive oxygen species promotes neurodegeneration and whether blockade of these damaging factors can prevent abnormal glial and neuronal functions in models of disease and inflammatory cascades. Dr. Orr's research program has received generous support from the NIH K99/R00 Pathway to Independence Award, Alzheimer’s Association, Leon Levy Foundation, Kellen Foundation, and the Sanofi iAward.
As an undergraduate student at Allegheny College, I was fortunate to have supportive mentors and early opportunities to explore my own interests and conduct independent research projects. Through these efforts, I learned how the brain processes information, generates emotions and memories, and drives our everyday choices and beliefs. I was especially fascinated by non-neuronal cells of the brain, called glia. These mysterious brain cells sparked my curiosity, because so little was known about their functions but increasing evidence implicated these cells in mental health. For my graduate studies, I spearheaded new methods to isolate and analyze glial cells, and discovered unexpected properties of glial receptors in brain inflammation. These studies revealed that glia can rapidly shift how they respond to brain injury and contribute to disease. These findings had intriguing implications for neurodegenerative disorders, which I was eager to explore in my postdoctoral work at the Gladstone Institutes.
As a postdoctoral fellow, I focused on the roles of glial signaling in Alzheimer’s disease and discovered that glial cells have abnormal signaling in disease that can cause memory loss. These findings were extremely exciting, because they demonstrated how non-neuronal cells can alter behavior and mental health. I also conducted a preclinical proof-of-concept study to begin translating these findings into a therapeutic strategy for memory loss. In addition to research, I also had opportunities in my training to be a mentor and raise awareness for Alzheimer’s disease, which were some of the most rewarding and memorable experiences. Participating in local fundraising efforts was especially eye opening and reminded me that scientific progress and testing of new medical treatments would not be possible without the dedicated support from donors and organizations like the BrightFocus Foundation. I am deeply grateful to everyone that contributes their resources and time to help us understand and prevent dementia.
First published on: June 12, 2019
Last modified on: July 2, 2019