title: The neuroprotective effects of milk fat globule-EGF factor 8 against oligomeric amyloid β toxicity.
abstract: BACKGROUND
  Phosphatidylserine receptor is a key molecule that mediates the phagocytosis of apoptotic cells. Milk fat globule-EGF factor 8 (MFG-E8) is a phosphatidylserine receptor that is expressed on various macrophage lineage cells, including microglia in the central nervous system (CNS). Targeted clearance of degenerated neurons by microglia is essential to maintain healthy neural networks. We previously showed that the CX3C chemokine fractalkine is secreted from degenerated neurons and accelerates microglial clearance of neuronal debris via inducing the release of MFG-E8. However, the mechanisms by which microglia produce MFG-E8 and the precise functions of MFG-E8 are unknown.
  
  
  METHODS
  The release of MFG-E8 from microglia treated with conditioned medium from neurons exposed to neurotoxic substances, glutamate or oligomeric amyloid β (oA β) was measured by ELISA. The neuroprotective effects of MFG-E8 and MFG-E8-induced microglial phagocytosis of oA β were assessed by immunocytochemistry. The effects of MFG-E8 on the production of the anti-oxidative enzyme hemeoxygenase-1 (HO-1) were determined by ELISA and immunocytochemisty.
  
  
  RESULTS
  MFG-E8 was induced in microglia treated with conditioned medium from neurons that had been exposed to neurotoxicants, glutamate or oA β. MFG-E8 significantly attenuated oA β-induced neuronal cell death in a primary neuron-microglia coculture system. Microglial phagocytosis of oA β was accelerated by MFG-E8 treatment due to increased CD47 expression in the absence of neurotoxic molecule production, such as tumor necrosis factor-α, nitric oxide, and glutamate. MFG-E8-treated microglia induced nuclear factor E(2)-related factor 2 (Nrf2)-mediated HO-1 production, which also contributed to neuroprotection.
  
  
  CONCLUSIONS
  These results suggest that microglia release MFG-E8 in response to signals from degenerated neurons and that MFG-E8 protects oA β-induced neuronal cell death by promoting microglial phagocytic activity and activating the Nrf2-HO-1 pathway. Thus, MFG-E8 may have novel roles as a neuroprotectant in neurodegenerative conditions.
authors: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors: Endong
authors: E
authors: Li
authors: Mariko
authors: M
authors: Noda
authors: Yukiko
authors: Y
authors: Doi
authors: Bijay
authors: B
authors: Parajuli
authors: Jun
authors: J
authors: Kawanokuchi
authors: Yoshifumi
authors: Y
authors: Sonobe
authors: Hideyuki
authors: H
authors: Takeuchi
authors: Tetsuya
authors: T
authors: Mizuno
authors: Akio
authors: A
authors: Suzumura
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D000954:Antigens, Surface / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D018920:Coculture Techniques; D006017:Glycolipids / Q000378:metabolism / Q000502:physiology* / Q000627:therapeutic use; D006023:Glycoproteins / Q000378:metabolism / Q000502:physiology* / Q000627:therapeutic use; D006801:Humans; D066292:Lipid Droplets; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D008894:Milk Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D061251:Primary Cell Culture
chemical_list: D016229:Amyloid beta-Peptides; D000954:Antigens, Surface; D006017:Glycolipids; D006023:Glycoproteins; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C110367:milk fat globule