Glial net around amyloid plaques in Alzheimer's

Researchers have made a significant breakthrough in Alzheimer’s disease research by identifying a novel way to potentially slow down or even halt disease progression. The study, which focuses on the role of reactive astrocytes and the plexin-B1 protein in Alzheimer's pathophysiology, provides crucial insights into brain cell communication and opens the door to innovative treatment strategies. It was published in Nature Neuroscience

This groundbreaking work is centered on the manipulation of the plexin-B1 protein to enhance the brain's ability to clear amyloid plaques, a hallmark of Alzheimer’s disease. Reactive astrocytes, a type of brain cell that becomes activated in response to injury or disease, were found to play a crucial role in this process.

The authors show that reactive astrocytes control cell distancing in peri-plaque glial nets, which restricts microglial access to amyloid deposits. This process is governed by guidance receptor Plexin-B1 (PLXNB1), a network hub gene in individuals with late-onset AD that is upregulated in plaque-associated astrocytes.

Plexin-B1 deletion in a mouse AD model led to reduced number of reactive astrocytes and microglia in peri-plaque glial nets, but higher coverage of plaques by glial processes, along with transcriptional changes signifying reduced neuroinflammation.

In addition, a reduced footprint of glial nets was associated with overall lower plaque burden, a shift toward dense-core-type plaques and reduced neuritic dystrophy.

“Our findings offer a promising path for developing new treatments by improving how cells interact with these harmful plaques,” said a senior author of the study. The research was driven by the analysis of complex data comparing healthy individuals to those with Alzheimer’s, aiming to understand the disease's molecular and cellular foundations.

One of the study’s lead authors, highlighted the broader implications of their findings: “Our study opens new pathways for Alzheimer’s research, emphasizing the importance of cellular interactions in developing neurodegenerative disease treatments.” 

One of the study’s most significant achievements is its validation of multiscale gene network models of Alzheimer’s disease. “This study not only confirms one of the most important predictions from our gene network models but also significantly advances our understanding of Alzheimer’s. It lays a solid foundation for developing novel therapeutics targeting such highly predictive network models,” said the other lead author. By demonstrating the critical role of plexin-B1 in Alzheimer's disease, the research underscores the potential of targeted therapies to disrupt the disease's progression.

The research team emphasizes that while their findings mark a significant advance in the fight against Alzheimer’s, more research is needed to translate these discoveries into treatments for human patients.

“Our ultimate goal is to develop treatments that can prevent or slow down Alzheimer’s progression,” the author added, outlining the team’s commitment to further exploring the therapeutic potential of plexin-B1.