Scientists have discovered that the brain may have a built-in way to fight Alzheimer's.
By activating a protein called Sox9, researchers were able to switch on star-shaped brain cells known as astrocytes and turn them into powerful cleaners that remove toxic plaques linked to memory loss. Tests in mice that already had Alzheimer's-like symptoms showed that boosting this protein helped clear out these harmful deposits and protect their memory.
Astrocytes and a Surprising Plaque-Clearing Mechanism
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 and help maintain memory and thinking ability. This process relies on astrocytes, star-shaped brain cells that can clear away the toxic plaques commonly found in Alzheimer's. When the researchers increased production of Sox9, a protein that guides many astrocyte functions as the brain ages, these cells became more effective at eliminating amyloid buildup. The findings, published today (November 21) in Nature Neuroscience, point to the possibility of developing treatments that strengthen astrocyte activity to slow cognitive decline in neurodegenerative conditions.
"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 was at the Center for Cell and Gene Therapy and the Department of Neurosurgery at Baylor while he was working on this project. Choi currently is 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.
Decoding How Aging Astrocytes Change
In this study, the team set out to uncover how aging affects astrocytes and how those changes relate to Alzheimer's disease. They focused on Sox9 because it acts as a key regulator for many genes in aging astrocytes.
"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," said 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, a member of the Dan L Duncan Comprehensive Cancer Center at Baylor and a principal investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital.
Testing Sox9 in Mice With Existing Cognitive Decline
"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 Alzheimer's models, the researchers either increased or removed Sox9 and then monitored the cognitive abilities of individual mice for six months, tracking how well they recognized familiar objects or environments. When the study concluded, the team examined the animals' brains to evaluate the amount of plaque that had accumulated.
Boosting Sox9 Reverses Plaque Build-Up and Cognitive Loss
Compared to reducing Sox9 expression, increasing it had the opposite effect. Sox9 knockout accelerated plaque formation, reduced astrocyte complexity and decreased clearance of amyloid deposits. Overexpression reversed these trends, promoting plaque clearance, while increasing the cells' activity and complexity. Importantly, overexpression of Sox9 also preserved cognitive function in these mice, indicating that astrocytic clearance of plaques halts neurodegenerative-related cognitive decline.
"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."
A Path Toward Astrocyte-Powered Therapies
Choi, Deneen, and their colleagues caution that more research is needed to understand how Sox9 works in the human brain over time. But their work opens the door to therapies that could one day harness the power of astrocytes to fight neurodegenerative diseases.
Reference: "Astrocytic Sox9 overexpression in Alzheimer's disease mouse models promotes Aβ plaque phagocytosis and preserves cognitive function" 21 November 2025, Nature Neuroscience.
DOI: 10.1038/s41593-025-02115-w
A number of additional researchers at Baylor College of Medicine played key roles in this project, including 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.
Funding for the study came from several National Institutes of Health grants (R35-NS132230, R01-AG071687, R01-CA284455, K01-AG083128, R56-MH133822). The project also received support 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.
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