Researchers at Baylor College of Medicine have identified a mechanism in mouse models of Alzheimer’s disease that helps clear amyloid plaques from the brain and preserves cognitive function. The study, published in Nature Neuroscience, focuses on astrocytes—star-shaped brain cells—and the role of the protein Sox9 in regulating their activity.
According to Dr. Dong-Joo Choi, first author of the study, “Astrocytes perform diverse tasks that are essential for normal brain function, including facilitating brain communications and memory storage. As the brain ages, astrocytes show profound functional alterations; however, the role these alterations play in aging and neurodegeneration is not yet understood.” Choi conducted this research while at Baylor and is now an assistant professor at the University of Texas Health Science Center at Houston.
The researchers investigated how changes in Sox9 expression affect astrocyte function during aging and in Alzheimer’s disease models. Dr. Benjamin Deneen, corresponding author and professor at Baylor College of Medicine, said, “We manipulated the expression of the Sox9 gene to assess its role in maintaining astrocyte function in the aging brain and in Alzheimer’s disease models.”
The team used mouse models that had already developed cognitive impairment and amyloid plaques. “An important point of our experimental design is that we worked with mouse models of Alzheimer’s disease that had already developed cognitive impairment, such as memory deficits, and had amyloid plaques in the brain,” Choi said. “We believe these models are more relevant to what we see in many patients with Alzheimer’s disease symptoms than other models in which these types of experiments are conducted before the plaques form.”
Over a six-month period, researchers altered Sox9 levels and evaluated mice for changes in memory and plaque accumulation. They found that reducing Sox9 led to faster plaque formation and decreased clearance by astrocytes. In contrast, increasing Sox9 promoted plaque removal by astrocytes and preserved cognitive abilities.
Dr. Deneen explained: “We found that increasing Sox9 expression triggered astrocytes to ingest more amyloid plaques, clearing them from the brain like a vacuum cleaner. Most current treatments focus on neurons or try to prevent the formation of amyloid plaques. This study suggests that enhancing astrocytes’ natural ability to clean up could be just as important.”
The authors note that further research is needed to understand how Sox9 functions over time in humans but suggest this approach could inform future therapies targeting neurodegenerative diseases.
Additional contributors from Baylor College of Medicine include Sanjana Murali, Wookbong Kwon, Junsung Woo, Eun-Ah Christine Song, Yeunjung Ko, Debo Sardar, Brittney Lozzi, Yi-Ting Cheng, Michael R. Williamson, Teng-Wei Huang, Kaitlyn Sanchez and Joanna Jankowsky.
The project received funding from several National Institutes of Health grants as well as support from private foundations and joint resources from Houston Methodist and Baylor College of Medicine.
