Department of Biochemistry, University of Cambridge, Cambridge, UK.
J Neurochem. 2013 Aug;126(3):312-7. doi: 10.1111/jnc.12288. Epub 2013 May 22.
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.
纳米摩尔浓度的β-淀粉样肽（Aβ）可通过激活小胶质细胞吞噬神经元，导致培养中的神经元丧失。我们在此报告，这种神经元丧失是由桥连蛋白乳脂肪球表皮生长因子 8（MFG-E8）介导的，Aβ 激活的小胶质细胞释放 MFG-E8，与共培养的神经元结合，并调理神经元使其被小胶质细胞吞噬。Aβ 刺激小胶质细胞吞噬，但不调理神经元进行吞噬。Aβ（250 nM）诱导混合神经胶质-神经元小鼠培养物中的延迟性神经元丧失，这需要小胶质细胞参与，且不会增加神经元凋亡或坏死。MFG-E8 抗体可预防这种神经元死亡/丧失，而 Mfge8 基因敲除小鼠（留下存活神经元）的培养物中不存在这种死亡/丧失，并且添加重组 MFG-E8 后可恢复。因此，纳米摩尔浓度的 Aβ 通过诱导小胶质细胞吞噬本来存活的神经元，引发神经元死亡，而这一过程需要 MFG-E8。毫摩尔浓度的 Aβ 的直接神经毒性不受 MFG-E8 影响。MFG-E8 在 Aβ 诱导的吞噬作用中具有重要作用，表明该桥连蛋白可能成为预防阿尔茨海默病神经元丧失的潜在治疗靶点。
