The neuroprotective effects of milk fat globule-EGF factor 8 against oligomeric amyloid β toxicity

Journal of Neuroinflammation

Akio Suzumura¹  Tetsuya Mizuno¹  Hideyuki Takeuchi¹  Yoshifumi Sonobe¹  Jun Kawanokuchi¹  Bijay Parajuli¹  Yukiko Doi¹  Mariko Noda¹  Endong Li¹ 

[1] Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan

关键词: Nrf2;    MFG-E8;    Neuroprotection;    Microglia;   

Others  :  1212470
DOI  :  10.1186/1742-2094-9-148

 received in 2012-02-23, accepted in 2012-05-01,  发布年份 2012

【 摘 要 】

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 (oAβ) was measured by ELISA. The neuroprotective effects of MFG-E8 and MFG-E8 − induced microglial phagocytosis of oAβ 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 oAβ. MFG-E8 significantly attenuated oAβ-induced neuronal cell death in a primary neuron − microglia coculture system. Microglial phagocytosis of oAβ 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 oAβ-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.

【 授权许可】

   
2012 Li et al.; licensee BioMed Central Ltd.

【 图 表 】

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