Regulation of tau pathology by the microglial fractalkine receptor.
Regulation of tau pathology by the microglial fractalkine receptor.
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DOI：
10.1016/j.neuron.2010.08.023
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发表时间：
2010-10-06
期刊：
影响因子：
16.2
通讯作者：
Lamb, Bruce T.
中科院分区：
文献类型：
--
作者：
Bhaskar, Kiran;Konerth, Megan;Kokiko-Cochran, Olga N.;Cardona, Astrid;Ransohoff, Richard M.;Lamb, Bruce T.
过度磷酸化的微管相关蛋白tau的聚集体(MAPT)是tau病的一个不变的神经病理特征。在这里，我们发现小胶质细胞神经炎促进了MAPT的磷酸化和聚集。首先，脂多糖诱导的小胶质细胞激活促进非转基因小鼠内源性MAPT的过度磷酸化，在缺乏小胶质细胞特异性Fractalkine受体(CX3CR1)的小鼠中进一步增强，并依赖于功能上的Toll样受体4和白介素1(IL1)受体。其次，缺乏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p38MAPK水平增加相关的行为损伤。第三，体外实验表明，小胶质细胞的激活提高了活跃的p38MAPK水平，并增强了神经元内MAPT的过度磷酸化，这可以被白介素1受体拮抗剂和特定的p38MAPK抑制剂所阻断。综上所述，我们的结果表明，CX3CR1和IL1/p38MAPK可能成为治疗人类紧张症的新靶点。
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 non-transgenic 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 (IL1) 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 IL1/p38 MAPK may serve as novel therapeutic targets for human tauopathies.
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DOI：
10.1073/pnas.95.18.10896
发表时间：
1998-09-01
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
8.6
作者：
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通讯作者：
Brooks, DJ
影响因子：
4.7
作者：
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通讯作者：
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