Researchers at Baylor College of Medicine have identified a natural process in the brain that can remove existing amyloid plaques in mouse models of Alzheimer's disease while also helping preserve memory and thinking ability. This process relies on astrocytes, star shaped support cells, which can be guided to clear out the toxic plaque buildup commonly seen in Alzheimer's. When the team increased the amount of Sox9, a protein that influences many astrocyte functions during aging, the cells became more effective at removing amyloid deposits. The findings, reported in Nature Neuroscience, suggest that strengthening astrocyte activity could one day help slow cognitive decline linked to neurodegenerative disorders.
"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," said first author Dr. Dong-Joo Choi, who conducted this work while at the Center for Cell and Gene Therapy and the Department of Neurosurgery at Baylor. Choi is now an assistant professor at the Center for Neuroimmunology and Glial Biology, Institute of Molecular Medicine at the University of Texas Health Science Center at Houston.
Focusing on Sox9 as a Key Regulator
For this project, the investigators set out to understand how astrocytes change with age and how those changes relate to Alzheimer's disease. Their attention centered on Sox9, a protein that influences a wide network of genes involved in astrocyte aging.
"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," explained corresponding author Dr. Benjamin Deneen, professor and Dr. Russell J. and Marian K. Blattner Chair in the Department of Neurosurgery, director of the Center for Cancer Neuroscience, member of the Dan L Duncan Comprehensive Cancer Center at Baylor and principal investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital.
Testing the Approach in Symptomatic Alzheimer's Models
"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."
In these models, the researchers either increased or removed Sox9 and then monitored each mouse's cognitive performance for six months. During this period, the animals were tested on their ability to recognize familiar objects and locations. After the behavioral studies were completed, the team examined the brains to measure plaque accumulation.
Higher Sox9 Levels Improve Plaque Removal and Memory
The results showed a clear difference. Lowering Sox9 led to faster plaque buildup, reduced structural complexity in astrocytes and diminished plaque clearing. Raising Sox9 had the opposite effect, increasing the cells' activity, supporting plaque removal and preserving cognitive performance. The protective benefits suggested that strong astrocyte engagement may help slow the cognitive decline associated with neurodegenerative disease.
"We found that increasing Sox9 expression triggered astrocytes to ingest more amyloid plaques, clearing them from the brain like a vacuum cleaner," Deneen said. "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."
Future Potential and Ongoing Research Needs
Choi, Deneen and their colleagues note that additional research is needed to understand how Sox9 behaves in the human brain across time. Still, these results point toward the possibility of developing therapies that harness astrocytes' natural cleaning abilities to combat neurodegenerative disorders.
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, all at Baylor College of Medicine, also contributed to this work.
This research was supported by National Institutes of Health grants (R35-NS132230, R01-AG071687, R01-CA284455, K01-AG083128, R56-MH133822). Additional funding came from the David and Eula Wintermann Foundation, the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number P50HD103555 and from shared resources provided by Houston Methodist and Baylor College of Medicine.
