Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice.
Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice.
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补体C3缺乏可防止老年斑块丰富的APP/PS1小鼠的神经退行性变
DOI：
10.1126/scitranslmed.aaf6295
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发表时间：
2017-05-31
影响因子：
17.1
通讯作者：
Lemere CA
中科院分区：
文献类型：
--
作者：
Shi Q;Chowdhury S;Ma R;Le KX;Hong S;Caldarone BJ;Stevens B;Lemere CA
补体级联反应是一种先天性免疫反应，可在外周免疫系统中清除病原体，同时在大脑发育过程中，对小胶质细胞介导的突触细化也起着重要作用。在阿尔茨海默病（AD）中，补体C3水平升高，与神经炎性斑块共定位，似乎有助于小胶质细胞清除β - 淀粉样蛋白（Aβ）；然而，目前尚不清楚C3是否在与斑块相关的突触和神经元健康方面发挥作用。此前，我们报道了C3缺陷型C57BL / 6小鼠在正常衰老过程中，可免受年龄及区域特异性海马突触丢失和认知能力下降的影响。此外，在年轻的阿尔茨海默病小鼠斑块积累之前的早期阶段，阻断补体及下游iC3b / CR3信号通路可挽救Aβ诱导的突触丢失。在此，我们评估了老年、富含斑块的APPswe / PS1dE9转基因小鼠（APP / PS1；C3基因敲除小鼠）中C3缺陷对AD晚期认知、Aβ斑块沉积及斑块相关神经病理学的影响。我们发现，16月龄的APP / PS1；C3基因敲除小鼠尽管脑内Aβ斑块更多，但在学习和记忆任务中的表现明显优于APP / PS1小鼠。与APP / PS1小鼠相比，老年APP / PS1；C3基因敲除小鼠海马Aβ斑块中心的小胶质细胞分支更多，且小胶质细胞和星形胶质细胞数量更少。APP / PS1；C3基因敲除小鼠脑内几种促炎细胞因子减少，这与小胶质细胞表型改变一致。即使在Aβ斑块增多的情况下，C3缺陷也能保护APP / PS1小鼠免受年龄依赖性突触和神经元丢失的影响。综上所述，我们的研究表明，补体C3或下游补体激活片段在APP / PS1小鼠大脑的斑块病理、胶质细胞对斑块的反应以及神经元功能障碍中发挥着重要作用。
尽管存在大量Aβ斑块，C3缺陷仍可保护老年AD小鼠免受海马神经退行性变和认知能力下降的影响。
The complement cascade is an innate immune response to remove pathogens in the peripheral immune system but also plays an important role in microglia-mediated synaptic refinement during brain development. Complement C3 is elevated in Alzheimer’s disease (AD), colocalizing with neuritic plaques, and appears to contribute to Aβ clearance by microglia; however, it is not known whether C3 plays a role in plaque-related synaptic and neuronal health. Previously, we reported that C3-deficient C57BL/6 mice were protected against age-and region-specific hippocampal synapse loss and cognitive decline during normal aging. Furthermore, blocking complement and downstream iC3b/CR3 signaling rescues synapses from Aβ-induced loss in early stages in young Alzheimer’s mice before plaques accumulate. Here, we assessed the effects of C3-deficiency in aged, plaque-rich APPswe/PS1dE9 Tg mice (APP/PS1;C3 KO) on cognition, Aβ plaque deposition and plaque-related neuropathology at later AD stages. We found that 16-month-old APP/PS1;C3 KO mice performed significantly better on a learning and memory task than APP/PS1 mice, despite having more cerebral Aβ plaques. Aged APP/PS1:C3 KO mice also had more ramified-looking microglial and fewer microglia and astrocytes localized within the center of hippocampal Aβ plaques compared to APP/PS1 mice. Several pro-inflammatory cytokines in brain were reduced in APP/PS1;C3 KO mouse brain, consistent with an altered microglial phenotype. C3-deficiency also protected APP/PS1 mice against age-dependent synapse and neuronal loss, even in the context of increased Aβ plaques. Taken together, our studies suggest that complement C3 or downstream complement activation fragments play an important role in plaque pathology, glial response to plaques and neuronal dysfunction in APP/PS1 mouse brains. C3-deficiency protects against hippocampal neurodegeneration and cognitive decline in aged AD mice despite the presence of abundant Aβ plaques.
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DOI：
10.3791/2270
发表时间：
2010-11-16
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Ippolito, Dominic M;Eroglu, Cagla
通讯作者：
Eroglu, Cagla
影响因子：
5.3
作者：
Lian, Hong;Litvinchuk, Alexandra;Zheng, Hui
通讯作者：
Zheng, Hui
影响因子：
2.9
作者：
HAGA, S;IKEDA, K;ISHII, T
通讯作者：
ISHII, T
影响因子：
2.9
作者：
Choucair-Jaafar, Nada;Laporte, Vincent;Gies, Jean-Pierre
通讯作者：
Gies, Jean-Pierre
DOI：
10.1016/0923-2494(92)80044-l
发表时间：
1992-07-01
期刊：
RESEARCH IN IMMUNOLOGY
影响因子：
--
作者：
EIKELENBOOM, P;HACK, CE;ROZEMULLER, JM
通讯作者：
ROZEMULLER, JM