The participation of interleukin-6, a stress-inducible cytokine, in the pathogenesis of Alzheimer's disease
The participation of interleukin-6, a stress-inducible cytokine, in the pathogenesis of Alzheimer's disease
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DOI：
10.1016/0166-4328(95)00213-8
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发表时间：
1996-06-01
影响因子：
2.7
通讯作者：
Bauer, J
中科院分区：
文献类型：
--
作者：
Hull, M;Strauss, S;Bauer, J
失智症患者大脑皮层中突触的丢失似乎是阿尔茨海默病（AD）的主要相关因素。然而，目前尚不清楚突触病理学如何与其他病理学发现，如AD中的神经元性和神经炎性变性或炎症标志物相关联。白细胞介素-6（IL-6）免疫反应性先前已在AD患者脑中的斑块中检测到。此外，在AD患者的脑中已经生化地测量了升高的IL-6浓度。由于在脑特异性启动子的控制下携带额外IL-6基因拷贝的转基因小鼠发展出显著的皮质病理学，包括皮质神经元树突状分支的严重改变，因此IL-6相关炎症事件很可能与AD中的突触病理学有关。在这项研究中，我们调查了是否IL-6免疫反应性斑块可以已经发现神经炎性变化的发病前，或是否存在这种细胞因子被限制到斑块形成的后期阶段。虽然弥漫性斑块代表斑块形成的早期阶段，但原始和经典斑块（显示神经炎病理）被认为反映了斑块病理的后期阶段。使用银染色方法，我们分类斑块阶段的石蜡包埋的皮质的临床诊断和组织病理学证实的AD患者和对照组的人没有痴呆的临床病史的连续切片。相邻切片用针对IL-6的抗体染色。IL-6在斑块的显著比例中可检测到，但仅在痴呆患者的大脑中。在AD病例中，在弥漫性斑块中发现IL-6的比例显著较高，这与IL-6在所有斑块类型中的随机分布所预期的一样。这一观察结果表明，IL-6的表达可能先于神经炎的变化，并在AD的免疫机制可能参与从弥漫性原始斑块的转化和痴呆的发展。AD患者脑中IL-6表达增加的原因尚不清楚。基础IL-6水平被发现在沿着正常老化过程中略有升高。基于几项研究表明，IL-6的表达也是由心理应激诱导的，人们可以推测长期的应激经历是否可能有助于阿尔茨海默病的病理过程。
A loss of synapses in the cortices of demented persons appears to be the primary correlate of Alzheimer's disease (AD). However, it is still unclear how synaptic pathology is connected to other pathological findings such as neurofibrillary and neuritic degeneration or inflammatory markers in AD. Interleukin-6 (IL-6) immunoreactivity has previously been detected in plaques in the brains of AD patients. Ln addition, elevated IL-6 concentrations have been measured biochemically in the brains of AD patients. Since transgenic mice bearing additional copies of the IL-6 gene under the control of a brain-specific promoter develop a marked cortical pathology including severe alterations of the dendritic arborization of cortical neurons, an IL-6 related inflammatory event could well be connected to the synaptic pathology in AD. In this study, we investigated whether IL-6 immunoreactivity in plaques could already be found prior to the onset of neuritic changes, or whether the presence of this cytokine is restricted to the later stages of plaque formation. While diffuse plaques represent an early stage of plaque formation, primitive and classic plaques (displaying neuritic pathology) are thought to reflect later stages of plaque pathology. Using a silver-staining method, we classified plaque stages in serial sections of paraffin-embedded cortices of clinically diagnosed and histopathologically confirmed AD patients and of control persons with no clinical history of dementia. Adjacent sections were stained with an antibody directed against IL-6. IL-6 was detectable in a significant proportion of plaques, but only in the brains of demented patients. In the AD cases, IL-6 was found in diffuse plaques in a significantly higher ratio as would have been expected from a random distribution of IL-6 among all plaque types. This observation suggests that IL-6 expression may precede neuritic changes and that in AD an immunological mechanism may be involved both in the transformation from diffuse to primitive plaques and in the development of dementia. The reasons for the increased expression of IL-6 in the brains of AD patients are still unknown. Basal IL-6 levels were found to be slightly elevated along normal aging. Based on several studies indicating that IL-6 expression is inducible also by psychological stress, one could speculate whether long-lasting stressful experiences may contribute to the pathological process underlying Alzheimer's disease.