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

Victor Bodart-Santos; Zhi Ruan; Bridgette C Melvin; Ikshu Pandey; Seiko Ikezu; Tsuneya Ikezu

doi:10.1016/j.celrep.2024.115025

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

Cell Rep. 2024 Nov 30;43(12):115025. doi: 10.1016/j.celrep.2024.115025. Online ahead of print.

Authors

Victor Bodart-Santos¹, Zhi Ruan¹, Bridgette C Melvin¹, Ikshu Pandey², Seiko Ikezu¹, Tsuneya Ikezu³

Affiliations

¹ Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
² Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
³ Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA; Regenerative Science Graduate Program, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA; Robert and Alene Kogod Center on Aging, Mayo Clinic, Jacksonville, FL 32224, USA; Alzheimer's Disease Research Center, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: ikezu.tsuneya@mayo.edu.

PMID: 39616613
DOI: 10.1016/j.celrep.2024.115025

Abstract

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 APP^NL-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 APP^NL-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.

Keywords: Alzheimer’s disease; CD63; CD9; CP: Cell biology; CP: Neuroscience; animal model; exosome; extracellular vesicles; lysosome; microglia; selenoprotein P; transcriptome.