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Updated: Jul 9, 2025
Author Spotlight: In Vitro Co-Culture Model for Studying Microglia-Neuronal Interactions in Disease Conditions
Published on: July 26, 2024
Microglia Mediate Contact-Independent Neuronal Network Remodeling via Secreted Neuraminidase-3 Associated with
Corleone S Delaveris1, Catherine L Wang1, Nicholas M Riley1
1Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, California 94305, United States.
Abstract:
Neurons communicate with each other through electrochemical transmission at synapses. Microglia, the resident immune cells of the central nervous system, modulate this communication through a variety of contact-dependent and -independent means. Microglial secretion of active sialidase enzymes upon exposure to inflammatory stimuli is one unexplored mechanism of modulation. Recent work from our lab showed that treatment of neurons with bacterial sialidases disrupts neuronal network connectivity. Here, we find that activated microglia secrete neuraminidase-3 (Neu3) associated with fusogenic extracellular vesicles. Furthermore, we show that Neu3 mediates contact-independent disruption of neuronal network synchronicity through neuronal glycocalyx remodeling. We observe that NEU3 is transcriptionally upregulated upon exposure to inflammatory stimuli and that a genetic knockout of NEU3 abrogates the sialidase activity of inflammatory microglial secretions. Moreover, we demonstrate that Neu3 is associated with a subpopulation of extracellular vesicles, possibly exosomes, that are secreted by microglia upon inflammatory insult. Finally, we demonstrate that Neu3 is necessary and sufficient to both desialylate neurons and decrease neuronal network connectivity. These results implicate Neu3 in remodeling of the glycocalyx leading to aberrant network-level activity of neurons, with implications in neuroinflammatory diseases such as Parkinson's disease and Alzheimer's disease.
Insights
Activated microglia release neuraminidase-3 (Neu3) via extracellular vesicles, disrupting neuronal network connectivity by remodeling the neuronal glycocalyx. This finding has implications for neuroinflammatory diseases.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia are immune cells in the central nervous system that modulate neuronal communication.
- Microglial secretion of sialidase enzymes is an unexplored mechanism influencing neuronal networks.
- Neuronal network connectivity can be disrupted by sialidases, as shown by previous bacterial sialidase treatments.
Purpose of the Study:
- To investigate the role of microglial sialidase secretion in modulating neuronal network activity.
- To identify specific sialidase enzymes secreted by activated microglia.
- To elucidate the mechanism by which microglial secretions affect neuronal network synchronicity.
Main Methods:
- Analysis of microglial secretions for sialidase activity.
- Genetic knockout of the neuraminidase-3 (Neu3) gene in microglia.
- Characterization of extracellular vesicles secreted by activated microglia.
- Assessment of neuronal network synchronicity and glycocalyx structure.
Main Results:
- Activated microglia secrete neuraminidase-3 (Neu3) associated with extracellular vesicles.
- NEU3 is upregulated in microglia upon inflammatory stimulation.
- Microglial Neu3 mediates contact-independent disruption of neuronal network synchronicity via glycocalyx remodeling.
- Genetic knockout of NEU3 eliminates sialidase activity in microglial secretions and prevents network disruption.
Conclusions:
- Neuraminidase-3 (Neu3) secreted by activated microglia, particularly within extracellular vesicles, disrupts neuronal network connectivity.
- Neu3's mechanism involves remodeling the neuronal glycocalyx, leading to aberrant network activity.
- These findings suggest a role for microglial Neu3 in neuroinflammatory conditions like Parkinson's and Alzheimer's diseases.
