Deficiency of macrophage migration inhibitory factor attenuates tau hyperphosphorylation in mouse models of Alzheimer's disease.
Deficiency of macrophage migration inhibitory factor attenuates tau hyperphosphorylation in mouse models of Alzheimer's disease.
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DOI：
10.1186/s12974-015-0396-3
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发表时间：
2015-09-17
影响因子：
9.3
通讯作者：
Ye RD
中科院分区：
文献类型：
--
作者：
Li SQ;Yu Y;Han JZ;Wang D;Liu J;Qian F;Fan GH;Bucala R;Ye RD
阿尔茨海默病（Alzheimer's disease，AD）的病理特征包括淀粉样蛋白β（amyloid beta，Aβ）和tau蛋白的聚集。巨噬细胞移动抑制因子（MIF）是一种促炎细胞因子，与聚集的Aβ的毒性有关。目前尚不清楚MIF是否影响tau蛋白的过度磷酸化和聚集。在侧脑室注射链脲佐菌素（STZ）的Mif−/−小鼠和与Mif−/−小鼠交配的APP/PS1转基因小鼠中，研究了MIF缺陷对tau蛋白过度磷酸化的影响。使用免疫荧光染色在ICV-STZ小鼠中评价MIF表达和星形胶质细胞活化。培养的原代星形胶质细胞用高糖处理以模拟体外STZ功能，并收集条件培养基（CM）。使用蛋白质印迹法测定用星形胶质细胞CM处理的神经元中tau过度磷酸化的水平。MIF缺陷减弱小鼠tau蛋白过度磷酸化。侧脑室注射STZ可增加海马星形胶质细胞活化和MIF表达。MIF缺乏减弱ICV-STZ小鼠星形胶质细胞活化。高糖处理的WT星形胶质细胞的CM增加了培养的原代神经元中tau的过度磷酸化，这是Mif−/−星形胶质细胞和用MIF抑制剂ISO-1处理的WT星形胶质细胞所不存在的效应。在培养的原代神经元中，ISO-1对tau蛋白磷酸化没有直接影响。这些结果表明，MIF缺陷与测试的小鼠AD模型中星形胶质细胞活化和tau蛋白过度磷酸化减少有关。抑制MIF和MIF诱导的星形胶质细胞活化可能有助于AD的预防和治疗。本文的在线版本（doi：10.1186/s12974-015-0396-3）包含补充材料，可供授权用户使用。
Pathological features of Alzheimer’s disease (AD) include aggregation of amyloid beta (Aβ) and tau protein. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, has been implicated in the toxicity of aggregated Aβ. It remains unclear whether MIF affects hyperphosphorylation and aggregation of tau. The effects of MIF deficiency in tau hyperphosphorylation were examined in Mif−/− mice receiving intracerebroventricular (ICV) injection of streptozotocin (STZ) and in APP/PS1 transgenic mice mated with Mif−/− mice. MIF expression and astrocyte activation were evaluated in ICV-STZ mice using immunofluorescence staining. Cultured primary astrocytes were treated with high glucose to mimic STZ function in vitro, and the condition medium (CM) was collected. The level of tau hyperphosphorylation in neurons treated with the astrocyte CM was determined using Western blotting. MIF deficiency attenuated tau hyperphosphorylation in mice. ICV injection of STZ increased astrocyte activation and MIF expression in the hippocampus. MIF deficiency attenuated astrocyte activation in ICV-STZ mice. CM from high glucose-treated WT astrocytes increased tau hyperphosphorylation in cultured primary neurons, an effect absent from Mif−/− astrocytes and WT astrocytes treated with the MIF inhibitor ISO-1. ISO-1 had no direct effect on tau phosphorylation in cultured primary neurons. These results suggest that MIF deficiency is associated with reduced astrocyte activation and tau hyperphosphorylation in the mouse AD models tested. Inhibition of MIF and MIF-induced astrocyte activation may be useful in AD prevention and therapy. The online version of this article (doi:10.1186/s12974-015-0396-3) contains supplementary material, which is available to authorized users.