Suppression of LPS-induced tau hyperphosphorylation by serum amyloid A.
Suppression of LPS-induced tau hyperphosphorylation by serum amyloid A.
复制标题
血清淀粉样蛋白 A 抑制 LPS 诱导的 tau 过度磷酸化
DOI：
10.1186/s12974-016-0493-y
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发表时间：
2016-02-02
影响因子：
9.3
通讯作者：
Ye RD
中科院分区：
文献类型：
--
作者：
Liu J;Wang D;Li SQ;Yu Y;Ye RD
过度磷酸化tau的积累是包括阿尔茨海默病（AD）在内的tau蛋白病的主要神经病理学特征。血清淀粉样蛋白A（SAA）是一种具有类胡萝卜素性质的急性时相蛋白，与淀粉样蛋白沉积有关。目前尚不清楚SAA是否影响tau蛋白过度磷酸化。通过脑内注射SAA和全身给予脂多糖（LPS）的Saa 3 −/−小鼠，研究了SAA在tau过度磷酸化中的潜在参与。使用实时PCR和/或免疫荧光染色在这些小鼠中评估诱导的SAA表达和小胶质细胞活化。用来自SAA刺激的原代小胶质细胞的条件培养基（CM）处理培养的原代神经元细胞。使用蛋白质印迹法测定tau过度磷酸化的改变。Saa 3是LPS诱导的SAA蛋白在小鼠脑中与神经元共定位的主要形式。通过脑内注射SAA的过表达减弱了脑中tau蛋白的过度磷酸化。相反，Saa 3缺陷增强了由全身LPS施用诱导的tau蛋白磷酸化。脑内注射SAA也可诱导脑内小胶质细胞的活化。从SAA刺激的小胶质细胞释放到CM的IL-10减弱了培养的原代神经元中tau蛋白的过度磷酸化。IL-10中和抗体逆转SAA在减弱tau磷酸化中的作用。LPS诱导的SAA蛋白在脑中的表达导致小胶质细胞的活化和IL-10的释放，这反过来抑制了全身性炎症小鼠模型中的tau过度磷酸化。本文的在线版本（doi：10.1186/s12974-016-0493-y）包含补充材料，可供授权用户使用。
Accumulation of hyperphosphorylated tau is a major neuropathological feature of tauopathies including Alzheimer’s disease (AD). Serum amyloid A (SAA), an acute-phase protein with cytokine-like property, has been implicated in amyloid deposition. It remains unclear whether SAA affects tau hyperphosphorylation. Potential involvement of SAA in tau hyperphosphorylation was examined using intracerebral injection of SAA, and in Saa3−/− mice receiving systemic administration of lipopolysaccharide (LPS). Induced SAA expression and microglial activation were evaluated in these mice using real-time PCR and/or immunofluorescence staining. Cultured primary neuronal cells were treated with condition media (CM) from SAA-stimulated primary microglial cells. The alteration in tau hyperphosphorylation was determined using Western blotting. Saa3 is the predominant form of SAA proteins induced by LPS in the mouse brain that co-localizes with neurons. Overexpression of SAA by intracerebral injection attenuated tau hyperphosphorylation in the brain. Conversely, Saa3 deficiency enhanced tau phosphorylation induced by systemic LPS administration. Intracerebral injection of SAA also induced the activation of microglia in the brains. IL-10 released to CM from SAA-stimulated microglia attenuated tau hyperphosphorylation in cultured primary neurons. IL-10 neutralizing antibody reversed the effect of SAA in the attenuation of tau phosphorylation. LPS-induced expression of SAA proteins in the brain leads to the activation of microglia and release of IL-10, which in turn suppresses tau hyperphosphorylation in a mouse model of systemic inflammation. The online version of this article (doi:10.1186/s12974-016-0493-y) contains supplementary material, which is available to authorized users.