Microglia Mediate Contact-Independent Neuronal Network Remodeling via Secreted Neuraminidase-3 Associated with Extracellular Vesicles
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.