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Updated: Jul 17, 2025
A Novel In Vitro Live-imaging Assay of Astrocyte-mediated Phagocytosis Using pH Indicator-conjugated Synaptosomes
Published on: February 5, 2018
Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8
Makis Tzioras1, Michael J D Daniels1, Caitlin Davies1
1UK Dementia Research Institute, the University of Edinburgh, Edinburgh EH8 9JZ, UK; Centre for Discovery Brain Sciences, the University of Edinburgh, Edinburgh EH8 9JZ, UK.
Abstract:
Synapse loss correlates with cognitive decline in Alzheimer's disease (AD). Data from mouse models suggests microglia are important for synapse degeneration, but direct human evidence for any glial involvement in synapse removal in human AD remains to be established. Here we observe astrocytes and microglia from human brains contain greater amounts of synaptic protein in AD compared with non-disease controls, and that proximity to amyloid-β plaques and the APOE4 risk gene exacerbate this effect. In culture, mouse and human astrocytes and primary mouse and human microglia phagocytose AD patient-derived synapses more than synapses from controls. Inhibiting interactions of MFG-E8 rescues the elevated engulfment of AD synapses by astrocytes and microglia without affecting control synapse uptake. Thus, AD promotes increased synapse ingestion by human glial cells at least in part via an MFG-E8 opsonophagocytic mechanism with potential for targeted therapeutic manipulation.
Insights
Alzheimer's disease (AD) brains show glial cells, including astrocytes and microglia, engulfing more synapses. This synapse ingestion is linked to amyloid plaques and APOE4, suggesting a therapeutic target for AD cognitive decline.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Synapse loss is a hallmark of Alzheimer's disease (AD), correlating with cognitive decline.
- While mouse models implicate microglia in synapse loss, direct human evidence of glial involvement in synapse removal in AD is lacking.
Purpose of the Study:
- To investigate the role of human astrocytes and microglia in synapse removal in Alzheimer's disease.
- To determine if amyloid-β plaques and APOE4 influence glial synapse engulfment.
- To explore the mechanism behind glial synapse phagocytosis in AD.
Main Methods:
- Analysis of synaptic protein content in human astrocytes and microglia from AD and control brains.
- In vitro co-culture experiments with human glial cells and synapses from AD patients and controls.
- Investigation of the role of MFG-E8 in glial synapse phagocytosis.
Main Results:
- Human astrocytes and microglia in AD brains contain significantly more synaptic protein than in controls.
- Proximity to amyloid-β plaques and the presence of the APOE4 gene exacerbate this synaptic protein accumulation.
- Both human astrocytes and microglia phagocytose synapses from AD patients more readily than control synapses in culture.
- Inhibition of MFG-E8 interactions reduced the engulfment of AD synapses by glial cells.
Conclusions:
- Human glial cells, including astrocytes and microglia, actively engulf synapses in Alzheimer's disease.
- This process is enhanced by amyloid-β plaques and the APOE4 risk gene.
- The MFG-E8 opsonophagocytic pathway plays a role in AD-associated glial synapse ingestion, presenting a potential therapeutic target.
