Astrocytes clear amyloid plaques and preserve cognitive function in Alzheimer’s mouse models

Researchers at Baylor College of Medicine have discovered a natural mechanism that clears existing amyloid plaques in the brains of mouse models of Alzheimer’s disease and preserves cognitive function. The mechanism involves recruiting brain cells known as astrocytes, star-shaped cells in the brain, to remove the toxic amyloid plaques that build up in many Alzheimer’s disease brains.

Increasing the production of Sox9, a key protein that regulates astrocyte functions during aging, triggered the astrocytes’ ability to remove amyloid plaques. The study, published in Nature Neuroscience, suggests a potential astrocyte-based therapeutic approach to ameliorate cognitive decline in neurodegenerative disease.

“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.

In the current study, researchers looked to identify mechanisms associated with astrocyte aging and Alzheimer’s disease, focusing on Sox9, as this protein is a top regulator of multiple 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.

“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 mice, the team overexpressed or eliminated Sox9 and then assessed the cognitive function of individual mice for six months, evaluating the animals’ ability to recognize objects or places. At the end of the experiment, the researchers measured plaque deposition in the brains.

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.”

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.

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.