The brain may have more of its own cleanup crew than scientists thought.
Researchers at Baylor College of Medicine say they found a built-in process that can remove existing amyloid plaques from the brains of mouse models of Alzheimer’s disease and help preserve memory and thinking ability. Their study, published in Nature Neuroscience, focused on astrocytes, star-shaped support cells in the brain that can be directed to clear away toxic plaque deposits commonly seen in Alzheimer’s.
The team found that increasing levels of Sox9, a protein that regulates astrocyte activity during aging, improved the cells’ ability to remove amyloid plaques.
“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.
Researchers said 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.
The experiments used mouse models of Alzheimer’s disease that had already developed cognitive impairment, including memory deficits, and had amyloid plaques in the brain.
“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.”
The researchers either increased or eliminated Sox9 in the mice and tracked their cognitive performance over six months. The animals were tested on their ability to recognize familiar objects and environments. At the end of the study, the team measured how much plaque had built up in the brain.
Lower Sox9 levels led to faster plaque buildup, simpler astrocyte structure and a reduced ability to clear amyloid deposits, the researchers said. Increasing Sox9 had the opposite effect, enhancing astrocyte activity, improving structural complexity and promoting plaque removal.
“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.”
Mice with higher Sox9 levels also maintained better cognitive function over time, according to the study.
Additional contributors from Baylor College of Medicine were 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 and R56-MH133822.
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