Boosting a regulatory protein allows brain cells to clear Alzheimer’s plaques in mice

A new study identifies a biological process that empowers specific brain cells to eliminate harmful proteins associated with Alzheimer’s disease. By increasing the levels of a specific regulatory protein in mice, scientists successfully cleared existing brain plaque and halted memory loss. These findings appear in the journal Nature Neuroscience.

The brain relies on a vast network of cells to maintain its daily function. While neurons often receive the most attention for their role in transmitting signals, they are supported by a population of star-shaped cells called astrocytes. These cells were once viewed merely as a glue that held the nervous system together. Modern science now recognizes them as active participants in brain health. They facilitate communication between neurons and assist in memory storage.

Astrocytes undergo significant physical and functional changes as the brain ages. The relationship between these age-related shifts and neurodegenerative conditions has been a subject of intense study. A team of researchers at Baylor College of Medicine sought to understand this connection. The group included lead author Dong-Joo Choi and senior author Benjamin Deneen. They investigated how these cellular changes might influence the progression of diseases like Alzheimer’s.

The researchers focused their attention on a protein known as Sox9. This protein acts as a master regulator within the cell. It controls the activity of multiple genes responsible for astrocyte function during the aging process. The team hypothesized that manipulating this protein could alter how the brain responds to the toxic accumulation of proteins.

Alzheimer’s disease is characterized by the buildup of amyloid beta plaques. These are clumps of toxic proteins that accumulate between nerve cells. They disrupt cell function and are a hallmark of the disease’s pathology. The researchers wanted to see if astrocytes could be coaxed into removing these deposits.

Free daily newsletter

To test this, the team designed an experiment using mouse models of Alzheimer’s disease. They specifically selected mice that had already developed signs of the condition. These animals displayed memory deficits and possessed established amyloid plaques in their brains.

“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.”

This approach differs from many standard preclinical studies. Often, treatments are tested on animals before they show symptoms to see if prevention is possible. Testing on animals with established impairment better mimics the clinical reality for human patients. Most people receive a diagnosis only after significant biological changes have occurred.

The scientists manipulated the expression of the Sox9 gene in these mice. They created two distinct experimental groups to observe the effects. In one group, they eliminated the gene responsible for producing Sox9. In the second group, they induced the astrocytes to overproduce the protein.

The team then monitored the animals for a period of six months. They evaluated the cognitive health of individual mice using standard behavioral assessments. These tests measured the animals’ ability to recognize specific objects or remember distinct locations. Such tasks are commonly used to gauge memory and learning in rodents.

Following the behavioral testing, the researchers examined the brains of the mice. They utilized imaging techniques to quantify the amount of plaque deposition. This allowed them to correlate the physical state of the brain with the behavioral results.

The results revealed a distinct divergence between the two groups. Reducing Sox9 expression had detrimental effects on the brain tissue. The removal of this regulator accelerated the formation of amyloid plaques. It also resulted in astrocytes that were less structurally intricate.

Conversely, increasing Sox9 levels produced a beneficial outcome. The astrocytes in the overexpression group displayed greater complexity and activity. This heightened state triggered the cells to actively remove the amyloid deposits. The presence of Sox9 essentially instructed the astrocytes to clean the surrounding tissue.

“We found that increasing Sox9 expression triggered astrocytes to ingest more amyloid plaques, clearing them from the brain like a vacuum cleaner,” Deneen said.

This biological clearance translated directly to cognitive preservation. The mice with elevated Sox9 levels did not suffer the same memory loss as their counterparts. Their ability to recognize objects and places remained intact. This suggests that the physical removal of plaques by astrocytes can halt the cognitive decline associated with neurodegeneration.

The study also mapped the specific molecular pathway responsible for this cleaning process. The researchers found that Sox9 regulates a receptor called MEGF10. This receptor sits on the surface of the astrocyte. It enables the cell to perform phagocytosis, a process where the cell engulfs and digests foreign substances.

When Sox9 levels are high, the production of MEGF10 increases. This equips the astrocyte with the necessary machinery to consume the amyloid plaques. The researchers confirmed that this specific signaling pathway is sufficient to preserve cognitive function.

“Most current treatments focus on neurons or try to prevent the formation of amyloid plaques,” Deneen said. “This study suggests that enhancing astrocytes’ natural ability to clean up could be just as important.”

The findings represent a shift in potential therapeutic strategies. Many existing drug development efforts target neurons directly. Others attempt to stop the production of amyloid beta before it aggregates. This research points toward a different approach: harnessing the brain’s innate immune and maintenance systems to repair damage.

There are caveats to consider when interpreting these results. The study was conducted in mouse models, which do not perfectly replicate human biology. The timeframe of the study, while significant for a mouse, is short compared to the decades over which Alzheimer’s develops in humans.

The specific mechanisms of Sox9 in the human brain require further verification. Human astrocytes are larger and more diverse than those found in rodents. It is necessary to determine if the Sox9-MEGF10 pathway functions identically in human tissue.

The authors also note that the long-term effects of overexpressing Sox9 need investigation. While beneficial in the context of this study, the permanent alteration of a master regulator could have other physiological consequences. Future research will likely focus on how to transiently activate this pathway or target the MEGF10 receptor directly.

This work opens the door to a new class of astrocyte-based therapies. By understanding how these support cells change with age, scientists can identify new targets for intervention. The goal is to restore the brain’s youthful capacity for self-maintenance.

Deneen, Choi, and their colleagues emphasize that this is a step toward a broader understanding of neurodegeneration. The interplay between different cell types in the brain dictates the progression of disease. Focusing solely on neurons provides an incomplete picture of brain health.

The research highlights the importance of non-neuronal cells in the fight against dementia. As the global population ages, the prevalence of Alzheimer’s disease continues to rise. Novel approaches that address the underlying cellular dysfunction are urgently needed. This study provides a strong foundation for exploring how to turn the brain’s support cells into active defenders against disease.

The study, “Astrocytic Sox9 overexpression in Alzheimer’s disease mouse models promotes Aβ plaque phagocytosis and preserves cognitive function,” was authored by Dong-Joo Choi, Sanjana Murali, Wookbong Kwon, Junsung Woo, Eun-Ah Christine Song, Yeunjung Ko, Debosmita Sardar, Brittney Lozzi, Yi-Ting Cheng, Michael R. Williamson, Teng-Wei Huang, Kaitlyn Sanchez, Joanna Jankowsky & Benjamin Deneen.