Lactadherin/MFG‐E8 is essential for microglia‐mediated neuronal loss and phagoptosis induced by amyloid β

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.