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

Autor:	Delaveris CS; Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, California 94305, United States., Wang CL; Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, California 94305, United States., Riley NM; Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, California 94305, United States., Li S; Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, California 94305, United States., Kulkarni RU; Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, California 94305, United States., Bertozzi CR; Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, California 94305, United States.; Howard Hughes Medical Institute, Stanford, California 94305, United States.
Jazyk:	angličtina
Zdroj:	ACS central science [ACS Cent Sci] 2023 Oct 31; Vol. 9 (11), pp. 2108-2114. Date of Electronic Publication: 2023 Oct 31 (Print Publication: 2023).
DOI:	10.1021/acscentsci.3c01066
Abstrakt:	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. Competing Interests: The authors declare the following competing financial interest(s): C.R.B. is a co-founder and Scientific Advisory Board member of Lycia Therapeutics, Palleon Pharmaceuticals, Enable Bioscience, Redwood Biosciences (a subsidiary of Catalent), InterVenn Bio, GanNa Bio, OliLux Bio, Neuravid Therapeutics, Valora Therapeutics, and Firefly Bio, and is a member of the Board of Directors of Alnylam Pharmaceuticals and OmniAb. R.U.K. is a co-inventor on a patent related to voltage-gated imaging dyes. (© 2023 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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