Sustained interleukin-1β overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer's mouse model.
Sustained interleukin-1β overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer's mouse model.
复制标题
DOI：
10.1523/jneurosci.4361-12.2013
复制
发表时间：
2013-03-13
期刊：
影响因子：
--
通讯作者：
O'Banion MK
中科院分区：
文献类型：
--
作者：
Ghosh S;Wu MD;Shaftel SS;Kyrkanides S;LaFerla FM;Olschowka JA;O'Banion MK
神经炎症是阿尔茨海默病（AD）发病机制的重要组成部分，并与神经退行性变有关。白细胞介素1（IL-1）是中枢神经系统中的一种有效的炎性细胞因子，在人类AD中长期上调，并且被认为是驱动AD病理的恶性炎症循环的一部分。为了进一步了解IL-1β在AD发病机制中的作用，我们使用了我们实验室开发的持续IL-1β过表达诱导模型（IL-1βXAT）。AD的三重转基因小鼠模型（在其生命周期后期出现斑块和缠结）与IL-1βXAT小鼠一起繁殖，并在F1后代中评估IL-1β过表达对AD病理学的影响。在转基因表达1个月和3个月后，我们发现tau磷酸化显著增加，尽管淀粉样蛋白负荷减少约70-80%，斑块相关小胶质细胞增加4-6倍，以及炎症部位小胶质细胞活化增加的证据。我们还发现了p38 MAPK和GSK 3 β活性增加的证据，据信这有助于tau磷酸化。因此，神经炎症以相反的方式调节淀粉样蛋白和tau病理学，这表明它提供了淀粉样蛋白积累和tau变化之间的联系，并引起了对AD中免疫调节治疗的关注。
Neuroinflammation is an important component of Alzheimer’s disease (AD) pathogenesis and has been implicated in neurodegeneration. Interleukin 1 (IL-1), a potent inflammatory cytokine in the central nervous system, is chronically upregulated in human AD and believed to serve as part of a vicious inflammatory cycle that drives AD pathology. To further understand the role of IL-1β in AD pathogenesis, we used an inducible model of sustained IL-1β overexpression (IL-1βXAT) developed in our laboratory. The triple transgenic mouse model of AD, which develops plaques and tangles later in its life cycle, was bred with IL-1βXAT mice and effects of IL-1β overexpression on AD pathology were assessed in F1 progeny. After 1 and 3 months of transgene expression, we found robust increases in tau phosphorylation despite an approximately 70–80% reduction in amyloid load and 4–6 fold increase in plaque associated microglia, as well as evidence of greater microglial activation at the site of inflammation. We also found evidence of increased p38MAPK and GSK3β activity, which are believed to contribute to tau phosphorylation. Thus neuroinflammation regulates amyloid and tau pathology in opposing fashions, suggesting that it provides a link between amyloid accumulation and changes in tau, and raising concerns about the use of immunomodulatory therapies in AD.