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首页> 外文期刊>Journal of neuroinflammation >Contribution of complement activation pathways to neuropathology differs among mouse models of Alzheimer's disease
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Contribution of complement activation pathways to neuropathology differs among mouse models of Alzheimer's disease

机译：阿尔茨海默氏病小鼠模型中补体激活途径对神经病理学的贡献不同

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Background Complement proteins and activation products have been found associated with neuropathology in Alzheimer's disease (AD). Recently, a C5a receptor antagonist was shown to suppress neuropathology in two murine models of AD, Tg2576 and 3xTg. Previously, a genetic deficiency of C1q in the Tg2576 mouse model showed an accumulation of fibrillar plaques similar to the complement sufficient Tg2576, but reactive glia were significantly decreased and neuronal integrity was improved suggesting detrimental consequences for complement activation in AD. The goal of this study was to define the role of the classical complement activation pathway in the progression of pathology in the 3xTg mouse that develops tangles in addition to fibrillar plaques (more closely reflecting human AD pathology) and to assess the influence of complement in a model of AD with a higher level of complement hemolytic activity. Methods 3xTg mice deficient in C1q (3xTgQ-/-) were generated, and both 3xTg and 3xTgQ-/- were backcrossed to the BUB mouse strain which has higher in vitro hemolytic complement activity. Mice were aged and perfused, and brain sections stained for pathological markers or analyzed for proinflammatory marker expression. Results 3xTgQ-/- mice showed similar amounts of fibrillar amyloid, reactive glia and hyperphosphorylated tau as the C1q-sufficient 3xTg at the ages analyzed. However, 3xTg and 3xTgQ-/- on the BUB background developed pathology earlier than on the original 3xTg background, although the presence of C1q had no effect on neuropathological and pro-inflammatory markers. In contrast to that seen in other transgenic models of AD, C1q, C4 and C3 immunoreactivity was undetectable on the plaques of 3xTg in any background, although C3 was associated with reactive astrocytes surrounding the plaques. Importantly, properdin a component of the alternative complement pathway was associated with plaques in all models. Conclusions In contrast to previously investigated transgenic models of AD, development of neuropathology in 3xTg mice, which progresses much slower than other murine models, may not be influenced by fibrillar amyloid mediated activation of the classical complement pathway, suggesting that the alternative complement pathway activation or a C3-independent cleavage of C5 could account for the detrimental effects in these mice that are prevented by the C5a receptor antagonist. Furthermore, the paucity of complement activation may be a factor in the slower kinetics of progression of pathology in the 3xTg model of this disease.
机译：背景已经发现补体蛋白和激活产物与阿尔茨海默氏病（AD）的神经病理学有关。最近，C5a受体拮抗剂在两种小鼠AD模型Tg2576和3xTg中显示出抑制神经病理学的作用。以前，在Tg2576小鼠模型中C1q的遗传缺陷显示类似于补体足够的Tg2576的原纤维斑积聚，但反应性神经胶质细胞明显减少，神经元完整性得到改善，提示AD中补体激活的有害后果。这项研究的目的是定义经典补体激活途径在3xTg小鼠中的发展过程中的作用，该小鼠除了出现纤维斑块（更紧密地反映了人类AD病理学）外还会缠结，并评估补体对小鼠的影响。具有较高水平的补体溶血活性的AD模型。方法产生3xTg缺乏C1q的小鼠（3xTgQ-/-），并将3xTg和3xTgQ-/-回交至具有较高体外溶血补体活性的BUB小鼠品系。对小鼠进行老化和灌注，并对脑切片进行病理学标记染色或对促炎性标记表达进行分析。结果3xTgQ-/-小鼠在分析年龄时显示出与C1q充足的3xTg相似的原纤维淀粉样蛋白，反应性神经胶质和高磷酸化tau量。然而，尽管C1q的存在对神经病理学和促炎性标志物没有影响，但BUB背景上的3xTg和3xTgQ-/-的病理学发展要早于原始3xTg背景。与在AD的其他转基因模型中看到的相反，在任何背景下，在3xTg的斑块上都无法检测到C1q，C4和C3的免疫反应性，尽管C3与斑块周围的反应性星形胶质细胞相关。重要的是，在所有模型中，备解素是替代补体途径的组成部分均与斑块相关。结论与先前研究的AD转基因模型相反，3xTg小鼠的神经病理学发展比其他鼠模型慢得多，可能不受纤维状淀粉样蛋白介导的经典补体途径的激活的影响，提示替代性补体途径的激活或C5的不依赖C3的裂解可以解释这些小鼠中C5a受体拮抗剂阻止的有害作用。此外，在该疾病的3xTg模型中，补体激活的缺乏可能是病理学进展较慢动力学的一个因素。

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