A study conducted by UCLA comparing brain cells known as astrocytes in humans and mice found that mouse astrocytes are more resistant to oxidative stress, a harmful imbalance that is a mechanism behind many neurological diseases. A lack of oxygen triggers molecular repair mechanisms in these mouse astrocytes, but not in human astrocytes. In contrast, inflammation activates immune response genes in human astrocytes but not in mouse astrocytes.
Although the mouse is a ubiquitous laboratory model used in research into neurological diseases, results from studies in mice are not always applicable to humans. In fact, more than 90% of drug candidates showing preclinical prospects for neurological disorders fail tests in humans, in part due to a lack of knowledge about the differences in astrocytes and other brain cells between the two species.
Astrocytes are critical to the development and function of the brain and play an essential role in neurological diseases that are, however, not yet fully understood. Injury or infection causes astrocytes to transition from a resting state to a reactive state, where they can help repair the brain, but can also increase harmful inflammation.
Scientists examined developing cells purified from mouse and human brain tissue, as well as cells grown in serum-free cultures from astrocytes selected using an antibody-based method developed by the study correspondent.
This technique was necessary because the conventional method of selecting astrocytes by growing them in serum – a mixture of proteins, hormones, fats, and minerals – puts them in a reactive state similar to that caused by infection or injury. Using the researchers’ strategy, they were able to study the astrocytes in a healthy state and under controlled conditions of oxidative stress, oxygen starvation, and excessive inflammation.
The results have implications for basic and translational research on neurological diseases such as Alzheimer’s, Parkinson’s and amyotrophic lateral sclerosis – diseases whose underlying mechanisms include oxidative stress, oxygen starvation and excessive inflammation.
Because mouse astrocytes are better able to withstand oxidative stress, the authors suggest that laboratory models of neurodegeneration could be developed to reduce this resistance and make it more human-like. In addition, the ability of mouse astrocytes to repair in response to a lack of oxygen could suggest a new avenue for stroke research. And neuroscientists can approach preclinical studies more knowledgeably by considering differences in response to inflammation between mouse and human astrocytes, as well as metabolic differences identified in the study.
Jiwen Li, a UCLA postdoctoral fellow, is the lead author of the study, and the corresponding author is Ye Zhang, a UCLA Assistant Professor of Psychiatry and Bio-Behavioral Sciences and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and the UCLA Semel Institute for Neuroscience and Human Behavior. Other co-authors are Lin Pan, William Pembroke, Jessica Rexach, Marlesa Godoy, Michael Condro, Alvaro Alvarado, Mineli Harteni, Yen-Wei Chen, Linsey Stiles, Angela Chen, Ina Wanner, Xia Yang, Daniel Geschwind and Harley Kornblum, all from UCLA and Steven Goldman from the University of Rochester and the University of Copenhagen.
The study is published online in the journal Nature Communications.
The study was funded by the ARCS Foundation, the National Institutes of Health, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the WM Keck Foundation, the Wendy Ablon Trust, a UCLA Broad Stem Cell Research Center Innovation Award, and the Friends of the Semel Institute for Neuroscience and Human Behavior at UCLA.