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Assessing Retinal Microglial Phagocytic Function In Vivo Using a Flow Cytometry-based Assay
Published on: October 18, 2016
Lactadherin/MFG-E8 is essential for microglia-mediated neuronal loss and phagoptosis induced by amyloid β
1Department of Biochemistry, University of Cambridge, Cambridge, UK.
Abstract:
Nanomolar β-amyloid peptide (Aβ) can induce neuronal loss in culture by activating microglia to phagocytose neurons. We report here that this neuronal loss is mediated by the bridging protein lactadherin/milk-fat globule epidermal growth factor-like factor 8 (MFG-E8), which is released by Aβ-activated microglia, binds to co-cultured neurons and opsonizes neurons for phagocytosis by microglia. Aβ stimulated microglial phagocytosis, but did not opsonize neurons for phagocytosis. Aβ (250 nM) induced delayed neuronal loss in mixed glial-neuronal mouse cultures that required microglia and occurred without increasing neuronal apoptosis or necrosis. This neuronal death/loss was prevented by antibodies to MFG-E8 and was absent in cultures from Mfge8 knockout mice (leaving viable neurons), but was reconstituted by addition of recombinant MFG-E8. Thus, nanomolar Aβ caused neuronal death by inducing microglia to phagocytose otherwise viable neurons via MFG-E8. The direct neurotoxicity of micromolar Aβ was not affected by MFG-E8. The essential role of MFG-E8 in Aβ-induced phagoptosis, suggests this bridging protein as a potential therapeutic target to prevent neuronal loss in Alzheimer's disease.
Insights
Nanomolar amyloid-beta peptides trigger microglial cells to engulf neurons, causing neuronal loss. This process is mediated by the bridging protein MFG-E8, a potential therapeutic target for Alzheimer's disease.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Amyloid-beta (Aβ) peptides are implicated in Alzheimer's disease pathogenesis.
- Microglia, the brain's immune cells, play a critical role in neuroinflammation and neuronal health.
- Previous studies have indicated Aβ can induce neuronal loss, but the precise mechanisms remain under investigation.
Purpose of the Study:
- To elucidate the mechanism by which nanomolar concentrations of Aβ induce neuronal loss in vitro.
- To investigate the role of the bridging protein MFG-E8 in Aβ-mediated microglial phagocytosis of neurons.
Main Methods:
- Utilized mixed glial-neuronal cultures from mice.
- Administered nanomolar Aβ to cultures and assessed neuronal viability and apoptosis.
- Investigated the effect of MFG-E8 antibodies and Mfge8 knockout mice on Aβ-induced neuronal loss.
- Assessed microglial phagocytosis of neurons using co-culture systems.
Main Results:
- Nanomolar Aβ induced delayed neuronal loss in a microglia-dependent manner, without increasing apoptosis.
- This neuronal loss was prevented by antibodies against MFG-E8 and absent in Mfge8 knockout mice.
- Recombinant MFG-E8 addition reconstituted the Aβ-induced neuronal loss in knockout cultures.
- MFG-E8 was released by Aβ-activated microglia and opsonized neurons for phagocytosis.
Conclusions:
- Nanomolar Aβ induces neuronal death through phagoptosis, where microglia engulf viable neurons.
- MFG-E8 acts as a crucial bridging protein mediating this Aβ-induced phagoptosis.
- MFG-E8 represents a potential therapeutic target to prevent neuronal loss in Alzheimer's disease.
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