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

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Microglia, the brain's innate immune cells, contribute to neuroinflammation and protein aggregation spread via extracellular vesicles (EVs).
• Selenoprotein P (Sepp1) is implicated as a potential regulator of microglial EV secretion.

Purpose of the Study:

• To investigate the impact of Sepp1 silencing on microglial transcriptomics and elucidate its regulatory mechanism in EV secretion.
• To validate the effect of Sepp1 on EV secretion in a mouse model of Alzheimer's disease (APP^NL-G-F knockin mice).

Main Methods:

• Single-vesicle flow cytometry and super-resolution microscopy were used to quantify EV secretion and CD63 loading.
• Transcriptomic analysis of microglia following Sepp1 silencing.
• In vitro studies involving astrocytes and neurons, and in vivo studies in APP^NL-G-F mice.

Main Results:

• Sepp1 silencing significantly reduced EV secretion and CD63 loading in BV-2 microglia.
• Sepp1 deficiency led to downregulation of EV biogenesis machinery, increased lysosomal activity, and altered lipid metabolism.
• In vivo, Sepp1 silencing decreased EV secretion from microglia in APP^NL-G-F mouse brains.

Conclusions:

• Sepp1 plays a crucial role in regulating microglial EV secretion.
• Targeting Sepp1 may offer a therapeutic strategy to mitigate the spread of neurodegenerative pathologies mediated by microglial EVs.