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Updated: Jul 4, 2025
A Novel In Vitro Live-imaging Assay of Astrocyte-mediated Phagocytosis Using pH Indicator-conjugated Synaptosomes
Published on: February 5, 2018
Clearance of β-amyloid and synapses by the optogenetic depolarization of microglia is complement selective
Zezhong Lv1, Lixi Chen2, Ping Chen3
1Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Abstract:
Microglia actively monitor the neighboring brain microenvironments and constantly contact synapses with their unique ramified processes. In neurodegenerative diseases, including Alzheimer's disease (AD), microglia undergo morphological and functional alterations. Whether the direct manipulation of microglia can selectively or concurrently modulate synaptic function and the response to disease-associated factors remains elusive. Here, we employ optogenetic methods to stimulate microglia in vitro and in vivo. Membrane depolarization rapidly changes microglia morphology and leads to enhanced phagocytosis. We found that the optogenetic stimulation of microglia can efficiently promote β-amyloid (Aβ) clearance in the brain parenchyma, but it can also enhance synapse elimination. Importantly, the inhibition of C1q selectively prevents synapse loss induced by microglia depolarization but does not affect Aβ clearance. Our data reveal independent microglia-mediated phagocytosis pathways toward Aβ and synapses. Our results also shed light on a synergistic strategy of depolarizing microglia and inhibiting complement functions for the clearance of Aβ while sparing synapses.
Insights
Optogenetic stimulation of microglia enhances amyloid clearance but also synapse loss in Alzheimer's disease models. Inhibiting complement C1q selectively prevents synapse loss without impacting amyloid removal.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia, the brain's immune cells, monitor neural environments and interact with synapses.
- Microglia exhibit altered morphology and function in neurodegenerative diseases like Alzheimer's disease (AD).
- The precise control of microglial activity to modulate synaptic function and disease response is not fully understood.
Purpose of the Study:
- To investigate whether direct optogenetic manipulation of microglia can selectively or concurrently modulate synaptic function and response to disease-associated factors.
- To explore the independent or overlapping pathways microglia use to clear amyloid-beta and synapses.
Main Methods:
- Utilized optogenetic methods for microglia stimulation in vitro and in vivo.
- Observed rapid changes in microglia morphology and phagocytosis upon membrane depolarization.
- Assessed the impact of microglia stimulation and C1q inhibition on beta-amyloid (Aβ) clearance and synapse elimination.
Main Results:
- Optogenetic stimulation of microglia promoted Aβ clearance but also enhanced synapse elimination.
- Inhibition of complement C1q selectively prevented microglia-depolarization-induced synapse loss.
- C1q inhibition did not affect Aβ clearance, indicating independent phagocytosis pathways.
- Demonstrated distinct microglial pathways for Aβ and synapse phagocytosis.
Conclusions:
- Microglia-mediated phagocytosis of Aβ and synapses are independent processes.
- A synergistic strategy involving microglia depolarization and complement inhibition can clear Aβ while preserving synapses.
- This offers a potential therapeutic approach for Alzheimer's disease, balancing amyloid clearance and synaptic integrity.
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