In mice already losing memories to Alzheimer’s, scientists have uncovered a way to turn the brain’s star shaped support cells into sweeping cleaners that slow cognitive decline. By boosting a single protein called Sox9 inside astrocytes, a Baylor College of Medicine team found that the cells engulfed existing amyloid plaques and kept memory from worsening over months of testing.
The work, an experimental mouse study published in Nature Neuroscience by researchers at Baylor College of Medicine and Texas Children’s Hospital, centers on astrocytes and their shifting roles in aging and disease. Led by Dong Joo Choi and Benjamin Deneen, the team showed that increasing Sox9 in astrocytes activated a plaque clearing program, reduced plaque load across hippocampus and cortex, increased astrocyte complexity and lysosomal activity, and preserved performance in novel object, place recognition and working memory tasks. Using the APP NLGF model, the researchers intervened only after animals had developed visible brain plaques and measurable memory impairment, creating a closer analog to diagnosed human Alzheimer’s disease.
Astrocytes have long been cast as helpers rather than healers. They shape synapses, manage metabolic needs, and maintain barrier defenses around the brain’s vasculature. But as brains age or accumulate toxic proteins, these star shaped cells alter gene expression and circuit level responsibilities. Choi and colleagues used both transcriptomic profiling and chromatin mapping to show that Sox9 is a top regulatory hub in aging astrocytes, with distinct DNA binding patterns in young, aged and Alzheimer’s model tissue. When Sox9 was removed from astrocytes in older mice, the cells lost branching complexity, calcium activity fell, synaptic plasticity weakened, and plaque formation accelerated in Alzheimer’s models.
The reverse experiment proved more powerful. Viral delivery of Sox9 to astrocytes in mice with established amyloid plaques caused a marked drop in plaque burden within two months. Astrocytes extended more elaborate processes, surrounded plaques with lysosome rich compartments, and internalized greater amounts of amyloid beta. Detailed 3D imaging confirmed that Sox9 enriched astrocytes pulled plaque fragments into Lamp1 and cathepsin D positive vesicles, a signature of active phagocytosis.
A Shift in How the Brain Fights Its Own Debris
One crucial insight from the study is that astrocytes carry a built in phagocytic toolkit that can be amplified. Transcriptomic analysis pointed to MEGF10, an astrocyte specific phagocytic receptor, as a key Sox9 target. When the team knocked out Sox9, MEGF10 expression collapsed. When they boosted Sox9, MEGF10 rose sharply. Chromatin immunoprecipitation confirmed Sox9 binding at MEGF10 regulatory sites, linking the transcription factor directly to this clearance machinery. In follow up tests, direct overexpression of MEGF10 in Alzheimer’s model mice reduced plaque levels, improved discrimination in object and place recognition, and raised astrocytic phagocytosis indices, even when Sox9 itself was absent.
The mouse experiments were deliberately staged after pathology had begun, an important choice given how many Alzheimer’s studies intervene before plaques form. The researchers used behavioral tests every two months from age four to ten months, watching cognitive trajectories under differing astrocyte conditions. Mice receiving Sox9 overexpression did not return to wild type memory levels, but they maintained stable performance across four months while untreated Alzheimer’s model mice continued to decline. Synaptic and neuronal markers showed modest improvements in Sox9 enriched hemispheres, suggesting broader protection beyond plaque clearance.
“We found that increasing Sox9 expression triggered astrocytes to ingest more amyloid plaques, clearing them from the brain like a vacuum cleaner,”
By using the APP NLGF model, which develops plaques and memory impairment around the same timeline, the researchers emphasized clinical relevance. Astrocytes lacking Sox9 accumulated more plaques, exhibited less branching architecture, and showed reduced microglial support. In contrast, Sox9 enriched hemispheres exhibited less neuritic dystrophy and slightly higher neuronal survival. These structural findings matched the behavioral data and underscored a consistent theme: Sox9 helps aging and diseased astrocytes maintain their protective roles.
A Protective Plateau, Not a Cure
The researchers are careful not to oversell the findings. Sox9 overexpression did not restore lost memories, and it cannot halt the complex molecular cascade that defines Alzheimer’s pathology. Instead, the intervention appeared to stop decline, buying time in a system that ordinarily deteriorates steadily. This nuance may help explain another puzzle: Sox9 levels are already elevated in human Alzheimer’s tissue and in mouse models, yet plaques still form. The team proposes that early in disease progression, amyloid output overwhelms even heightened astrocytic responses. External Sox9 boosts may push astrocytes past their natural limit, enabling them to keep pace with rapid plaque deposition, at least for a while.
Choi frames this as a shift in experimental design as much as biology. “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,” he 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 work opens new avenues for targeting astrocytes rather than neurons in Alzheimer’s research. It also raises fundamental questions about transcription factor dependencies that shift across age, region and disease state. If Sox9 and MEGF10 can be safely tuned in human astrocytes, therapies may one day complement neuronal approaches by empowering the brain’s inherent cleaning systems. For now, the study offers a new view of Alzheimer’s progression and a reminder that sometimes the cells that seem like bystanders may be the most powerful responders.
Nature Neuroscience: 10.1038/s41593-025-02115-w
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