The neuroprotective effects of milk fat globule-EGF factor 8 against oligomeric amyloid β toxicity.
The neuroprotective effects of milk fat globule-EGF factor 8 against oligomeric amyloid β toxicity.
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DOI：
10.1186/1742-2094-9-148
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发表时间：
2012-06-28
影响因子：
9.3
通讯作者：
Suzumura A
中科院分区：
文献类型：
--
作者：
Li E;Noda M;Doi Y;Parajuli B;Kawanokuchi J;Sonobe Y;Takeuchi H;Mizuno T;Suzumura A
磷脂酰丝氨酸受体是介导凋亡细胞吞噬功能的关键分子。乳脂球-EGF因子8(MFG-E8)是一种磷脂酰丝氨酸受体，表达于多种巨噬细胞系细胞上，包括中枢神经系统(CNS)的小胶质细胞。小胶质细胞对变性神经元的靶向清除对于维持健康的神经网络是必不可少的。我们先前证明CX3C趋化因子Fractalkine是由变性神经元分泌的，并通过诱导MFG-E8的释放来加速小胶质细胞对神经元碎片的清除。然而，小胶质细胞产生MFG-E8的机制和MFG-E8的确切功能尚不清楚。用ELISA法检测神经毒性物质谷氨酸或低聚淀粉样蛋白β(OAβ)对条件培养液处理的小胶质细胞释放MFG-E8的影响。免疫细胞化学方法检测MFG-E8和MFG-E8 − 诱导的小胶质细胞吞噬OAβ的神经保护作用。用酶联免疫吸附试验和免疫细胞化学方法检测MFG-E8对HO-1抗氧化酶产生的影响。MFG-E8在小胶质细胞中被诱导，条件培养液来自暴露于神经毒物谷氨酸或OAβ的神经元。在原代神经元β小胶质细胞共培养体系中，MFG-E8显著减轻了OA − 诱导的神经细胞死亡。在缺乏肿瘤坏死因子-β、一氧化氮和谷氨酸等神经毒性分子产生的情况下，经MFG-E8处理后，由于CD47表达增加，小胶质细胞吞噬作用加快。MFG-E8 − 处理小胶质细胞诱导的核因子E(2) − 相关因子2(NRF2) − 介导HO-1的产生，这也有助于神经保护。这些结果表明，小胶质细胞释放MFG-E8以响应来自变性神经元的信号，并且MFG-E8通过促进小胶质细胞吞噬活性和激活NRF2-HO-1途径来保护β诱导的神经细胞死亡。因此，MFG-E8可能在神经退行性疾病中作为神经保护剂具有新的作用。
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. 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. 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. 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.
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DOI：
10.4049/jimmunol.182.1.581
发表时间：
2009-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Komura H;Miksa M;Wu R;Goyert SM;Wang P
通讯作者：
Wang P
影响因子：
4.8
作者：
De Felice, Fernanda G.;Velasco, Pauline T.;Klein, William L.
通讯作者：
Klein, William L.
DOI：
10.2174/187152710791012071
发表时间：
2010-04
期刊：
CNS & neurological disorders drug targets
影响因子：
--
作者：
Mandrekar-Colucci S;Landreth GE
通讯作者：
Landreth GE
影响因子：
5.3
作者：
Koenigsknecht, J;Landreth, G
通讯作者：
Landreth, G
影响因子：
6
作者：
Doi, Yukiko;Mizuno, Tetsuya;Suzumura, Akio
通讯作者：
Suzumura, Akio