Visualizing a New Type of Communication in the Brain
Image: NIH Images
Recent research from the lab of Yongjie Yang, a member of the Neuroscience and Cell, Molecular and Developmental Biology programs at Sackler and an Associate Professor in the Tufts Department of Neuroscience, will allow neuroscientists (and others) to visualize a new type of cell-cell communication in the brain. Dr. Yang and his lab have developed a new mouse tool which will facilitate investigation of exosome signaling in both healthy and diseased conditions. Their results were published recently in Nature Communications.
Exosomes are a type of small vesicle secreted from many different cell types, including the cells of the central nervous system (CNS). These exosomes can contain numerous types of signaling molecules, and can transfer these signals from cell to cell. Although exosomes have been studied in cell culture, it is much more difficult to study them in a living animal. By fusing a protein commonly found in exosomes (CD63) with a fluorescent reporter (GFP), the Yang lab was able to create a genetically modified mouse in which exosomes from specific cell types can be labeled for easy visualization under a microscope.
Using this new tool, the researchers investigated one function that exosomes, specifically exosomes from neurons, perform in the healthy brain. Previous work with neurons and astrocytes, the most abundant glial cells in the brain, in cell culture models showed that exosomes from neurons provide a crucial signal, the microRNA miR-124, to astrocytes, which increases the expression of a protein (GLT1) that allows astrocytes to maintain the balance of the neurotransmitter glutamate in the brain. Using the CD63-GFP mice to clearly label neuronal exosomes in the mouse CNS, the Yang lab showed that exosomes from neurons not only were transferred into astrocytes in vivo, but also contained the same miR-124 signal in vivo that upregulates GLT1 expression in astrocytes. Blocking the overall secretion of exosomes reduced the expression levels and function of GLT1, and inhibiting miR-124 selectively in astrocytes also reduced GLT1 expression. These results highlight the importance of exosomal signaling from neurons to astrocytes for maintaining normal astrocyte function and the balance of glutamate signaling in the brain.
In addition to its utility for investigating the roles of exosomes in normal brain function, the CD63-GFP mouse will be extremely useful in investigating the roles of exosomes in diseases of the nervous system. Several proteins that are associated with neurodegenerative diseases, such as amyloid β in Alzheimer’s disease and SOD1 in amyotrophic lateral sclerosis, have also been found associated with exosomes. It has even been hypothesized that exosomes may be one route by which these pathogenic proteins spread through the CNS in these neurodegenerative diseases. Understanding the nature of exosome dynamics in these diseases will likely provide insights into the pathology of these diseases, and may lead to improved diagnostic or therapeutic tools in the future.
Men Y, Yelick J, Jin S, Tian Y, Chiang MSR, Higashimori H, Brown E, Jarvis R, Yang Y. 2019. Exosome reporter mice reveal the involvement of exosomes in mediating neuron to astroglia communication in the CNS. Nat Commun. 10(1):4136. doi: 10.1038/s41467-019-11534-w. Abstract.
This story was written by Rachel Jarvis.