Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer's disease
Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer's disease
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DOI：
10.1523/jneurosci.2868-05.2005
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发表时间：
2005-09-28
影响因子：
5.3
通讯作者：
LaFerla, FM
中科院分区：
文献类型：
--
作者：
Kitazawa, M;Oddo, S;LaFerla, FM
炎症是阿尔茨海默病（AD）发病机制的重要组成部分。虽然不是这种疾病的始作俑者，但炎症作为一种驱动力，在调节神经病理方面发挥着关键作用。在这里，我们描述了AD转基因模型（3xTg-AD）大脑中小胶质细胞激活的时间过程，并确定了其与斑块和缠结病理的关系。我们发现小胶质细胞以进行性和年龄依赖性的方式被激活，这种激活与纤维淀粉样蛋白β -肽斑块积累和tau过度磷酸化的开始相关。为了确定小胶质细胞激活是否会加剧病理，我们将年轻的3xTg-AD小鼠暴露于脂多糖（LPS）中，这是一种已知的CNS炎症诱导剂。尽管淀粉样蛋白前体蛋白加工未受影响，但我们发现LPS显著诱导tau蛋白在特定位点过度磷酸化，这是由细胞周期蛋白依赖性激酶5 （cdk5）的激活介导的，通过增加p25片段的形成。我们进一步表明，罗斯科维汀（一种选择性和有效的cdk5抑制剂）可以显著阻断lps诱导的海马tau磷酸化。因此，这项研究清楚地表明，小胶质细胞的激活加剧了关键的神经病理特征，如缠结的形成。
Inflammation is a critical component of the pathogenesis of Alzheimer's disease (AD). Although not an initiator of this disorder, inflammation nonetheless plays a pivotal role as a driving force that can modulate the neuropathology. Here, we characterized the time course of microglia activation in the brains of a transgenic model of AD (3xTg-AD) and discerned its relationship to the plaque and tangle pathology. We find that microglia became activated in a progressive and age-dependent manner, and this activation correlated with the onset of fibrillar amyloid beta-peptide plaque accumulation and tau hyperphosphorylation. To determine whether microglial activation can exacerbate the pathology, we exposed young 3xTg-AD mice to lipopolysaccharide (LPS), a known inducer of CNS inflammation. Although amyloid precursor protein processing appeared unaffected, we find that LPS significantly induced tau hyperphosphorylation at specific sites that were mediated by the activation of cyclin-dependent kinase 5 (cdk5) through increased formation of the p25 fragment. We further show that administration of roscovitine, a selective and potent inhibitor of cdk5, markedly blocked the LPS-induced tau phosphorylation in the hippocampus. Therefore, this study clearly demonstrates that microglial activation exacerbates key neuropathological features such as tangle formation.