Researchers at Baylor College of Medicine have uncovered a built in process that can remove existing amyloid plaques from the brains of mouse models of Alzheimer’s disease while also helping preserve memory and thinking ability. The discovery centers on astrocytes, star shaped support cells in the brain, which can be directed to clear away the toxic plaque deposits commonly seen in Alzheimer’s.
The team found that increasing levels of Sox9, a protein that plays a major role in regulating astrocyte activity during aging, significantly improved these cells’ ability to remove amyloid plaques. The findings, published in Nature Neuroscience, point to a potential treatment strategy that focuses on boosting the brain’s own support system to slow cognitive decline in neurodegenerative disease.
Astrocytes and Brain Function
“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 the work while at Baylor’s Center for Cell and Gene Therapy and Department of Neurosurgery. 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.
Sox9 and Aging Astrocytes
In this study, researchers set out to better understand how astrocytes change with age and how those changes are linked to Alzheimer’s disease. They focused on Sox9 because it controls the activity of 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 in Mice With Established Symptoms
“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.”
To test their approach, the researchers either increased or eliminated Sox9 in these mice and tracked their cognitive performance over six months. The animals were evaluated on their ability to recognize familiar objects and environments. At the end of the study, the team measured how much plaque had accumulated in the brain.
Boosting Sox9 Improves Plaque Clearance and Memory
The results revealed a clear contrast. Lower Sox9 levels led to faster plaque buildup, simpler astrocyte structure and reduced ability to clear amyloid deposits. Increasing Sox9 produced the opposite outcome, enhancing astrocyte activity, improving their structural complexity and promoting plaque removal.
Importantly, mice with higher Sox9 levels maintained better cognitive function, suggesting that activating astrocytes to clear plaques can help slow the mental decline associated with Alzheimer’s 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.”
A New Direction for Alzheimer’s Treatment
The researchers emphasize that more work is needed to understand how Sox9 functions in the human brain over time. Even so, the findings open the door to new therapies that aim to harness astrocytes as a natural defense against neurodegenerative disease.
Research Team and Funding
Additional contributors to the study 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 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 shared resources from Houston Methodist and Baylor College of Medicine.
