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

J Neurochem. 2013 Aug;126(3):312-7. doi: 10.1111/jnc.12288. Epub 2013 May 22.

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.

Keywords: Alzheimer's disease; SED1; lactadherin; neuroinflammation; phosphatidylserine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Antigens, Surface / metabolism*
  • Cells, Cultured
  • Coculture Techniques
  • Immunohistochemistry
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / metabolism*
  • Milk Proteins / metabolism*
  • Neurons / metabolism*
  • Phagocytosis / physiology*
  • Rats
  • Rats, Wistar

Substances

  • Amyloid beta-Peptides
  • Antigens, Surface
  • Mfge8 protein, mouse
  • Milk Proteins