Shi Qiaoqiao, Chowdhury Saba, Ma Rong, Le Kevin X, Hong Soyon, Caldarone Barbara J, Stevens Beth, Lemere Cynthia A
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Building for Transformative Medicine, 9th Floor, 60 Fenwood Road, Boston, MA 02115, USA.
Harvard Medical School, Boston, MA 02115, USA.
Sci Transl Med. 2017 May 31;9(392). doi: 10.1126/scitranslmed.aaf6295.
The complement cascade not only is an innate immune response that enables removal of pathogens 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 clearance of Aβ by microglia in the brain. Previously, we reported that C3-deficient C57BL/6 mice were protected against age-related and region-specific loss of hippocampal synapses and cognitive decline during normal aging. Furthermore, blocking complement and downstream iC3b/CR3 signaling rescued synapses from Aβ-induced loss in young AD mice before amyloid plaques had accumulated. We assessed the effects of C3 deficiency in aged, plaque-rich APPswe/PS1dE9 transgenic mice (APP/PS1; KO). We examined the effects of C3 deficiency on cognition, Aβ plaque deposition, and plaque-related neuropathology at later AD stages in these mice. We found that 16-month-old APP/PS1; KO mice performed better on a learning and memory task than did APP/PS1 mice, despite having more cerebral Aβ plaques. Aged APP/PS1; KO mice also had fewer microglia and astrocytes localized within the center of hippocampal Aβ plaques compared to APP/PS1 mice. Several proinflammatory cytokines in the brain were reduced in APP/PS1; KO mice, consistent with an altered microglial phenotype. C3 deficiency also protected APP/PS1 mice against age-dependent loss of synapses and neurons. Our study suggests that complement C3 or downstream complement activation fragments may play an important role in Aβ plaque pathology, glial responses to plaques, and neuronal dysfunction in the brains of APP/PS1 mice.
补体级联反应不仅是一种先天性免疫反应，可促使病原体被清除，而且在大脑发育过程中，在小胶质细胞介导的突触精细化方面发挥重要作用。在阿尔茨海默病（AD）中，补体C3升高，与神经炎性斑块共定位，并且似乎有助于大脑中小胶质细胞清除Aβ。此前，我们报道C3缺陷的C57BL/6小鼠在正常衰老过程中可免受年龄相关的、区域特异性的海马突触丧失和认知衰退的影响。此外，在淀粉样斑块积累之前，阻断补体及下游iC3b/CR3信号传导可挽救年轻AD小鼠中Aβ诱导的突触丧失。我们评估了C3缺陷对老年、富含斑块的APPswe/PS1dE9转基因小鼠（APP/PS1；基因敲除）的影响。我们研究了C3缺陷对这些小鼠AD后期阶段认知、Aβ斑块沉积和斑块相关神经病理学的影响。我们发现，尽管16月龄的APP/PS1；基因敲除小鼠脑内Aβ斑块更多，但在学习和记忆任务中的表现比APP/PS1小鼠更好。与APP/PS1小鼠相比，老年APP/PS1；基因敲除小鼠位于海马Aβ斑块中心的小胶质细胞和星形胶质细胞也更少。APP/PS1；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。C3缺陷还保护APP/PS1小鼠免受年龄依赖性的突触和神经元丧失。我们的研究表明，补体C3或下游补体激活片段可能在APP/PS1小鼠大脑的Aβ斑块病理学、胶质细胞对斑块的反应以及神经元功能障碍中起重要作用。
