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Updated: Jun 28, 2025
Author Spotlight: In Vitro Co-Culture Model for Studying Microglia-Neuronal Interactions in Disease Conditions
Published on: July 26, 2024
Neuronal control of microglia through the mitochondria
A R Pereira-Santos1, Emanuel Candeias2, J D Magalhães1
1CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Ph.D. Programme in Biomedicine and Experimental Biology (PDBEB), Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal.
Abstract:
The microbial toxin β-N-methylamino-L-alanine (BMAA), which is derived from cyanobacteria, targets neuronal mitochondria, leading to the activation of neuronal innate immunity and, consequently, neurodegeneration. Although known to modulate brain inflammation, the precise role of aberrant microglial function in the neurodegenerative process remains elusive. To determine if neurons signal microglial cells, we treated primary cortical neurons with BMAA and then co-cultured them with the N9 microglial cell line. Our observations indicate that microglial cell activation requires initial neuronal priming. Contrary to what was observed in cortical neurons, BMAA was not able to activate inflammatory pathways in N9 cells. We observed that microglial activation is dependent on mitochondrial dysfunction signaled by BMAA-treated neurons. In this scenario, the NLRP3 pro-inflammatory pathway is activated due to mitochondrial impairment in N9 cells. These results demonstrate that microglia activation in the presence of BMAA is dependent on neuronal signaling. This study provides evidence that neurons may trigger microglia activation and subsequent neuroinflammation. In addition, we demonstrate that microglial activation may have a protective role in ameliorating neuronal innate immune activation, at least in the initial phase. This work challenges the current understanding of neuroinflammation by assigning the primary role to neurons.
Insights
Neurons initiate microglial activation and neuroinflammation via the toxin β-N-methylamino-L-alanine (BMAA). This neuronal signaling, driven by mitochondrial dysfunction, primes microglia, challenging current neuroinflammation models.
Area of Science:
- Neuroscience
- Toxicology
- Immunology
Background:
- The microbial toxin β-N-methylamino-L-alanine (BMAA) from cyanobacteria induces neurodegeneration by targeting neuronal mitochondria and activating innate immunity.
- The exact role of microglial dysfunction in BMAA-induced neurodegeneration is not fully understood.
- Investigating neuronal signaling to microglia is crucial for understanding neuroinflammation.
Purpose of the Study:
- To determine if neurons can signal microglial cells in response to BMAA exposure.
- To elucidate the mechanism by which BMAA affects neuronal-microglial communication.
- To explore the role of microglial activation in BMAA-mediated neuroinflammation.
Main Methods:
- Primary cortical neurons were treated with BMAA.
- BMAA-treated neurons were co-cultured with the N9 microglial cell line.
- Neuronal signaling and microglial activation pathways, including NLRP3, were analyzed.
Main Results:
- Microglial activation by BMAA requires prior neuronal priming.
- BMAA did not directly activate inflammatory pathways in microglial cells.
- Neuronal mitochondrial dysfunction, signaled by BMAA-treated neurons, triggered microglial activation and NLRP3 pathway induction.
- Microglial activation may offer initial protection against neuronal innate immune activation.
Conclusions:
- Neuronal signaling is essential for BMAA-induced microglial activation.
- Neurons play a primary role in initiating neuroinflammation in response to BMAA.
- Microglial activation might serve a protective function in the early stages of neuroinflammation.
