Gut-derived bacterial vesicles carrying lipopolysaccharide promote microglia-mediated synaptic pruning

Area of Science:

• Neuroscience
• Microbiology
• Immunology

Background:

• Growing evidence links gut microbiota (GM) to Alzheimer's disease (AD).
• Elevated lipopolysaccharide (LPS) levels are found in AD brains, but the mechanism of its transport across the blood-brain barrier (BBB) is unclear.
• Bacteria-derived extracellular vesicles (bEVs) are hypothesized to transport LPS across the BBB.

Purpose of the Study:

• To investigate the role of gut microbiota-derived extracellular vesicles (bEVs) in transporting lipopolysaccharide (LPS) across the blood-brain barrier (BBB).
• To elucidate the mechanism by which bEVs contribute to neuroinflammation and synaptic pruning in Alzheimer's disease (AD).

Main Methods:

• Extraction and measurement of LPS in bEVs from human and mouse feces and blood.
• In vivo imaging and immunofluorescence to confirm bEVs' transport across the BBB.
• In vitro and in vivo investigation of bEVs' role in microglial activation and synaptic pruning.

Main Results:

• Elevated LPS-containing bEVs were detected in the plasma of AD patients compared to healthy individuals.
• LPS-carrying bEVs were confirmed to traverse the BBB.
• These bEVs activated microglial Piezo1, leading to excessive synaptic pruning via the C1q-C3 complement pathway.

Conclusions:

• Gut microbiota-derived bEVs can cross the BBB, with LPS being crucial for this penetration.
• bEVs are closely associated with AD progression, mediating microglial activation and synaptic pruning.
• Microglial Piezo1 plays a role in bEV-induced excessive synaptic pruning, highlighting a novel pathway in AD pathogenesis.