Alzheimer's disease: illustration of the amyloid-beta 40 peptide (and others) accumulating to form amyloid fibrils that build up dense amyloid plaques.
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Icahn School of Medicine at Mount Sinai researchers report that they have identified a novel method to potentially slow or even halt progression of Alzheimer’s disease (AD) by manipulating cellular interactions of protein around myeloid plaques. The new findings, published in the journal Nature Neuroscience, focuses on the role of the reactive astrocytes and the plexin-B1 protein in AD pathophysiology and provides a new understanding of brain cell communication that could inform the development of new treatment strategies.

“We reveal here 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,” the researchers wrote. “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.”

Reactive astrocytes are a type of brain cell that become active in response to injury or disease and were found to play a crucial role in plexin-B1 protein’s power to enhance the brain’s ability to clear amyloid plaques.

“Our study opens new pathways for Alzheimer’s research, emphasizing the importance of cellular interactions in developing neurodegenerative disease treatments,” said one of the study’s lead authors Hongyan Zou, PhD, professor of neurosurgery, and neuroscience, at Icahn School of Medicine at Mount Sinai.

The team also showed that reduced footprint of glial nets was associated with overall lower plaque burden, a shift toward dense-core-type plaques and reduced neuritic dystrophy. “Altogether, our study demonstrates that Plexin-B1 regulates peri-plaque glial net activation in AD. Relaxing glial spacing by targeting guidance receptors may present an alternative strategy to increase plaque compaction and reduce neuroinflammation in AD.”

For their research, the investigators conducted a complex comparison of data between healthy individuals and those with AD. Beyond developing a better understanding of the cellular interactions that aid in clearing of amyloid plaques, the team also validated multiscale gene networks models of Alzheimer’s.

“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 Bin Zhang, PhD, a professor of Neurogenetics at Icahn Mount Sinai and another of the study’s lead authors. 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.

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