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首页> 外文期刊>Neuron >Regulation of tau pathology by the microglial fractalkine receptor.
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Regulation of tau pathology by the microglial fractalkine receptor.

机译：小胶质分数链蛋白受体调节tau病理。

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Aggregates of the hyperphosphorylated microtubule-associated protein tau (MAPT) are an invariant neuropathological feature of tauopathies. Here, we show that microglial neuroinflammation promotes MAPT phosphorylation and aggregation. First, lipopolysaccharide-induced microglial activation promotes hyperphosphorylation of endogenous mouse MAPT in nontransgenic mice that is further enhanced in mice lacking the microglial-specific fractalkine receptor (CX3CR1) and is dependent upon functional toll-like receptor 4 and interleukin-1 (IL-1) receptors. Second, humanized MAPT transgenic mice lacking CX3CR1 exhibited enhanced MAPT phosphorylation and aggregation as well as behavioral impairments that correlated with increased levels of active p38 MAPK. Third, in vitro experiments demonstrate that microglial activation elevates the level of active p38 MAPK and enhances MAPT hyperphosphorylation within neurons that can be blocked by administration of an interleukin-1 receptor antagonist and a specific p38 MAPK inhibitor. Taken together, our results suggest that CX3CR1 and IL-1/p38 MAPK may serve as novel therapeutic targets for human tauopathies.
机译：高磷酸化微管相关蛋白tau（MAPT）的聚集体是tauopathies的不变的神经病理学特征。在这里，我们表明小胶质细胞神经炎症促进MAPT磷酸化和聚集。首先，脂多糖诱导的小胶质细胞活化促进非转基因小鼠内源性小鼠MAPT的过度磷酸化，而在缺乏小胶质细胞特异性fractalkine受体（CX3CR1）的小鼠中进一步增强，并且依赖于功能性收费型受体4和白介素-1（IL-1） ）受体。第二，缺少CX3CR1的人源化MAPT转基因小鼠表现出增强的MAPT磷酸化和聚集以及与活性p38 MAPK水平升高相关的行为障碍。第三，体外实验表明，小胶质细胞激活可提高神经元内活性p38 MAPK的水平，并增强MAPT的磷酸化作用，而白细胞介素1受体拮抗剂和特定的p38 MAPK抑制剂可阻止神经元内MAPT的过度磷酸化。两者合计，我们的结果表明，CX3CR1和IL-1 / p38 MAPK可能作为人类tauopathies的新型治疗目标。

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