Selenoprotein P is a target for regulating extracellular vesicle biogenesis and secretion from activated microglia in vivo.

Microglia, brain innate immune cells, participate in the spread of inflammatory signals and aggregated proteins through secretion of extracellular vesicles (EVs). Selenoprotein P (Sepp1) is a potential regulator of microglial EV secretion. Here, we investigate the effect of Sepp1 silencing on microglial transcriptomics to elucidate the Sepp1 regulatory mechanism of EV secretion and validate this effect in APPNL-G-F knockin mice. Silencing of Sepp1 significantly reduces EV secretion and CD63 loading to EVs from BV-2 microglia, as determined by single-vesicle flow cytometry and super-resolution microscopy. Sepp1 deficiency downregulates EV biogenesis machinery, accompanied by increased lysosomal activity and lipid metabolism. Silencing of Sepp1 in astrocytes but not neurons suppresses EV secretion in vitro. Finally, Sepp1 silencing reduces EV secretion from activated neurodegenerative microglia associated with amyloid plaques in APPNL-G-F mouse brains in vivo. Sepp1 is thus an emerging therapeutic target for ameliorating microglia-mediated disease spread through EV secretion in neurodegenerative disorders.