Contribution of complement activation pathways to neuropathology differs among mouse models of Alzheimer's disease
Contribution of complement activation pathways to neuropathology differs among mouse models of Alzheimer's disease
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DOI：
10.1186/1742-2094-8-4
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发表时间：
2011-01-15
影响因子：
9.3
通讯作者：
Tenner, Andrea J.
中科院分区：
文献类型：
--
作者：
Fonseca, Maria I.;Chu, Shu-Hui;Tenner, Andrea J.
背景：补体蛋白及其活化产物与阿尔茨海默病（AD）的神经病理学有关。最近，C5 a受体拮抗剂显示出在两种AD小鼠模型Tg 2576和3xTg中抑制神经病理学。以前，在Tg 2576小鼠模型中C1 q的遗传缺陷显示了与补体充足的Tg 2576相似的纤维斑块的积累，但是反应性胶质细胞显著减少，神经元完整性得到改善，这表明AD中补体激活的有害后果。本研究的目的是确定经典补体激活途径在3xTg小鼠中病理学进展中的作用，所述小鼠除了纤维斑块外还形成缠结（更紧密地反映人AD病理学）并评估补体在具有较高水平补体溶血活性的AD模型中的影响。产生C1 q缺陷的3xTg小鼠（3xTgQ-/-），并将3xTg和3xTgQ-/-与具有更高体外溶血补体活性的BUB小鼠品系回交。小鼠年龄和灌注，和脑切片染色的病理标志物或分析促炎标志物expression.Results：3xTgQ-/-小鼠表现出类似的纤维状淀粉样蛋白，反应性神经胶质细胞和过度磷酸化的tau蛋白的C1 q-足够的3xTg在分析的年龄。然而，3xTg和3xTgQ-/-在BUB背景下比在原始3xTg背景下更早地发展病理学，尽管C1 q的存在对神经病理学和促炎标志物没有影响。在其他转基因模型中看到的AD，C1 q，C4和C3的免疫反应是不可检测的斑块上的3xTg在任何背景下，虽然C3与反应性星形胶质细胞周围的斑块。重要的是，备解素的替代补体途径的一个组成部分是与斑块在所有模型。与先前研究的AD转基因模型相反，3xTg小鼠中神经病理学的发展（其进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活化的影响，提示补体旁路途径激活或C5的C3非依赖性裂解可以解释这些小鼠中被C5 a受体拮抗剂阻止的有害作用。此外，补体激活的缺乏可能是该疾病的3xTg模型中病理进展动力学较慢的一个因素。
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.