A recent study published on May 27 in Nature Neuroscience sheds light on the crucial role of reactive astrocytes and the plexin-B1 protein in the pathophysiology of Alzheimer’s disease, offering potential pathways for innovative treatment strategies.
The groundbreaking research focuses on manipulating the plexin-B1 protein to enhance the brain’s capacity to clear amyloid plaques, a defining characteristic of Alzheimer’s disease. Reactive astrocytes, brain cells activated in response to injury or disease, were found to significantly influence this process by regulating the spacing around amyloid plaques. This spacing determines how effectively other brain cells can access and clear these harmful deposits.
“Our findings offer a promising path for developing new treatments by improving how cells interact with these harmful plaques,” stated Roland Friedel, PhD, Associate Professor of Neuroscience and Neurosurgery at Icahn Mount Sinai and senior author of the study.
The study compared complex data from healthy individuals and those with Alzheimer’s to understand the disease’s molecular and cellular foundations. Hongyan Zou, PhD, Professor of Neurosurgery and Neuroscience at Icahn Mount Sinai and one of the study’s lead authors, emphasized the broader implications: “Our study opens new pathways for Alzheimer’s research, emphasizing the importance of cellular interactions in developing neurodegenerative disease treatments.”
A significant achievement of the study 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 Bin Zhang, PhD, Willard T.C. Johnson Research Professor of Neurogenetics at Icahn Mount Sinai and lead author.
The research underscores the potential of targeted therapies to disrupt Alzheimer’s progression by demonstrating the critical role of plexin-B1 in the disease. However, the research team stresses the need for further studies to translate these findings into human treatments.
“Our ultimate goal is to develop treatments that can prevent or slow down Alzheimer’s progression,” Dr. Zhang added, highlighting the team’s commitment to exploring the therapeutic potential of plexin-B1.
The study received support from the NIH National Institute on Aging (NIA) grants U01AG046170 and RF1AG057440 and is part of the NIA-led Accelerating Medicines Partnership – Alzheimer’s Disease (AMP-AD) Target Discovery and Preclinical Validation program. This public-private partnership aims to shorten the time between the discovery of potential drug targets and the development of new drugs for Alzheimer’s treatment and prevention.
About the Research
Title: Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer’s disease
Abstract: Communication between glial cells profoundly impacts Alzheimer’s disease (AD) pathophysiology. The study reveals that reactive astrocytes control cell distancing in peri-plaque glial nets, which restrict microglial access to amyloid deposits. This process is governed by the guidance receptor Plexin-B1 (PLXNB1), a network hub gene in individuals with late-onset AD, upregulated in plaque-associated astrocytes. Plexin-B1 deletion in a mouse AD model led to fewer reactive astrocytes and microglia in peri-plaque glial nets, increased plaque coverage by glial processes, and reduced neuroinflammation. Additionally, a reduced glial net footprint correlated with lower plaque burden, a shift toward dense-core plaques, and reduced neuritic dystrophy. The study suggests that targeting guidance receptors to relax glial spacing may increase plaque compaction and reduce neuroinflammation in AD.