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Published on: December 26, 2016
Rab11A Depletion in Microglia-Derived Extracellular Vesicle Proteome upon Beta-Amyloid Treatment
Giuseppina Mignogna1, Cinzia Fabrizi2, Virginia Correani1
1Dipartimento di Scienze Biochimiche, Sapienza Università di Roma, Rome, Italy.
Abstract:
Microglia, the macrophage-like glial cells, behave as sentinels against exogenous pathogens invading the neural tissue. Their commitment is not only confined to the defensive function, but they also perform balancing trophic activities such as neuronal postnatal development, remodeling and pruning of synapses. Likewise, microglia-derived extracellular vesicles (EVs) can play strategic roles in maintaining a healthy brain by modulating neuronal activity and by controlling neurite outgrowth as well as innate immune response. Nevertheless, strong evidence also points to their role in the development of neurodegenerative pathologies such as Alzheimer's disease (AD). Here, we explored EV protein content released by BV2 microglial cells in a resting state and after stimulation with beta-amyloid peptides (Aβ), mimicking conditions occurring in AD. In the resting BV2 cells, we extended the list of proteins present in mouse microglia EV cargo with respect to those reported in the Vesiclepedia exosome database while, in amyloid-triggered microglia, we highlighted a pronounced drop in EV protein content. Focusing on Rab11A, a key factor in the recycling routes of amyloid species, we observed a dramatic decrease of this protein in Aβ-treated microglia EV cargo with respect to the EVs from the untreated sample. This decrease might affect the delivery of Rab11A to neurons thus increasing the harmful amyloid burden in neuronal cells that eventually may lead to their death. We tentatively proposed that alterations observed in EVs derived from Aβ-treated microglia may represent molecular features that, among others, shape the disease-associated microglial phenotype, a recently proposed subset of microglial population, present in neurodegenerative pathologies.
Insights
Microglia extracellular vesicles (EVs) play roles in brain health and neurodegenerative diseases like Alzheimer's. Amyloid-beta stimulation of microglia significantly reduced EV protein content, particularly Rab11A, potentially increasing neuronal amyloid burden.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia are crucial for brain defense and homeostasis, performing functions like synaptic remodeling.
- Microglia-derived extracellular vesicles (EVs) modulate neuronal activity, neurite outgrowth, and immune responses.
- Dysfunctional microglia and their EVs are implicated in neurodegenerative diseases, including Alzheimer's disease (AD).
Purpose of the Study:
- To investigate the protein cargo of extracellular vesicles (EVs) released by BV2 microglial cells under resting and amyloid-beta (Aβ) stimulated conditions.
- To identify changes in EV protein content associated with Alzheimer's disease-like pathology.
- To explore the role of specific proteins, such as Rab11A, in microglial EVs during Aβ exposure.
Main Methods:
- Cultured BV2 microglial cells were maintained in a resting state or stimulated with beta-amyloid peptides (Aβ).
- Extracellular vesicles (EVs) were isolated from the conditioned media of both resting and stimulated microglia.
- Proteomic analysis was performed on the isolated EVs to identify and quantify protein content, with a focus on Rab11A.
Main Results:
- The study expanded the known protein cargo of mouse microglia EVs from resting cells.
- Amyloid-beta stimulation led to a significant reduction in the overall protein content of microglial EVs.
- A marked decrease in Rab11A protein was observed in EVs from Aβ-treated microglia compared to untreated controls.
Conclusions:
- Alterations in microglial EV protein cargo, specifically the reduction of Rab11A, may contribute to neurodegeneration in AD.
- Reduced Rab11A in EVs could impair its delivery to neurons, exacerbating amyloid burden and neuronal death.
- These EV changes may represent key molecular features defining the disease-associated microglial phenotype in neurodegenerative conditions.
