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Brain penetration of peripheral extracellular vesicles from Alzheimer's patients and induction of microglia
Hermine Counil1, Rummenigge Oliveira Silva1, Jean-Michel Rabanel1,2
1INRS Centre Armand-Frappier Santé Biotechnologie Laval Quebec Canada.
Abstract:
Alzheimer's disease (AD) is an age-related neurodegenerative pathology. Brain-derived extracellular vesicles (EVs) have been demonstrated to be implicated in AD pathogenesis by facilitating the propagation of Tau, amyloid-β and inflammatory cytokines. However, the impact of peripheral EVs (pEVs) in AD pathogenesis remains poorly investigated. The objective of our study was to compare the passage of pEVs from adults, cognitively healthy elderly, and AD patients through the blood-brain barrier (BBB), to evaluate their uptake in the brain and to assess their impact on the microglia activity using in vitro and in vivo models. To this end, pEVs were enriched, characterized, and fluorescently labelled. The passage of pEVs through the endothelial bEnd.3 cells was studied in a Transwell device with either neuronal or microglia cells seeded at the bottom of the well. Following the internalization of pEVs from AD patients, microglia adopted an amoeboid morphology and released a heightened level of pro-inflammatory cytokine IL-6. To further assess their in vivo transport across the BBB, pEVs were injected into the blood circulation of 2-days post-fertilization Tg(flk1:EGFP) zebrafish. The biodistribution of pEVs was monitored at 1 and 24 h post-injection using confocal microscopy. We demonstrated that pEVs traverse the BBB by transcytosis and subsequently diffuse progressively into the brain. pEVs were then internalized by neuronal and radial glial cells as seen in Tg(huc:EGFP) and Tg(gfap:EGFP) zebrafish, respectively. Additional experiments were performed with the intrahippocampal injection of pEVs in the mouse, indicating their spreading throughout the brain and their uptake by neuronal and glial cells. These findings contribute to novel insights into the fate of pEVs following their passage through the BBB in vitro and in vivo, and demonstrate for the first time that pEVs from AD patients affect microglia activity. This suggests a potential mechanism through which peripheral tissue cues may contribute to AD pathogenesis.
Insights
Peripheral extracellular vesicles (EVs) from Alzheimer's disease (AD) patients cross the blood-brain barrier (BBB) and activate microglia. This suggests a novel pathway linking peripheral changes to AD neuroinflammation.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Alzheimer's disease (AD) is a neurodegenerative disorder.
- Brain-derived extracellular vesicles (EVs) are implicated in AD pathogenesis.
- The role of peripheral EVs (pEVs) in AD remains unclear.
Purpose of the Study:
- To investigate the passage of pEVs across the blood-brain barrier (BBB).
- To evaluate pEV uptake in the brain.
- To assess the impact of pEVs on microglia activity.
Main Methods:
- In vitro Transwell model using endothelial cells and neuronal/microglia co-cultures.
- In vivo studies using fluorescently labeled pEVs injected into zebrafish and mice.
- Confocal microscopy for biodistribution analysis.
- Assessment of microglia morphology and cytokine release (IL-6).
Main Results:
- Peripheral EVs (pEVs) from AD patients were shown to cross the BBB via transcytosis.
- pEVs were internalized by neuronal and glial cells in both zebrafish and mouse models.
- Internalization of pEVs from AD patients induced microglia activation and increased IL-6 release.
Conclusions:
- Peripheral EVs can traverse the BBB and impact brain cells.
- AD patient-derived pEVs can modulate microglia activity, suggesting a role in neuroinflammation.
- This study highlights a potential mechanism connecting peripheral factors to AD pathogenesis.
