Lerner Research Institute, The Cleveland Clinic, Department of Neurosciences, Case Western Reserve University School of Medicine, 9500 Euclid Avenue, NC30, Cleveland, OH 44195-0001, USA.
Am J Pathol. 2010 Nov;177(5):2549-62. doi: 10.2353/ajpath.2010.100265. Epub 2010 Sep 23.
Microglia, the primary immune effector cells in the brain, continually monitor the tissue parenchyma for pathological alterations and become activated in Alzheimer's disease. Loss of signaling between neurons and microglia via deletion of the microglial receptor, CX3CR1, worsens phenotypes in various models of neurodegenerative diseases. In contrast, CX3CR1 deficiency ameliorates pathology in murine stroke models. To examine the role of CX3CR1 in Alzheimer's disease-related β-amyloid pathology, we generated APPPS1 and R1.40 transgenic mouse models of Alzheimer's disease deficient for CX3CR1. Surprisingly, CX3CR1 deficiency resulted in a gene dose-dependent reduction in β-amyloid deposition in both the APPPS1 and R1.40 mouse models of AD. Immunohistochemical analysis revealed reduced staining for CD68, a marker of microglial activation. Furthermore, quantitative immunohistochemical analysis revealed reduced numbers of microglia surrounding β-amyloid deposits in the CX3CR1-deficient APPPS1 animals. The reduced β-amyloid pathology correlated with reduced levels of TNFα and CCL2 mRNAs, but elevated IL1β mRNA levels, suggesting an altered neuroinflammatory milieu. Finally, to account for these seemingly disparate results, both in vitro and in vivo studies provided evidence that CX3CL1/CX3CR1 signaling alters the phagocytic capacity of microglia, including the uptake of Aβ fibrils. Taken together, these results demonstrate that loss of neuron-microglial fractalkine signaling leads to reduced β-amyloid deposition in mouse models of AD that is potentially mediated by altered activation and phagocytic capability of CX3CR1-deficient microglia.
小胶质细胞是大脑中主要的免疫效应细胞，它们不断监测组织实质是否发生病理改变，并在阿尔茨海默病中被激活。通过删除小胶质细胞受体 CX3CR1，神经元与小胶质细胞之间的信号传递丧失，会使各种神经退行性疾病模型中的表型恶化。相反，CX3CR1 缺失可改善小鼠中风模型中的病理。为了研究 CX3CR1 在与阿尔茨海默病相关的 β-淀粉样蛋白病理中的作用，我们生成了 APPPS1 和 R1.40 转基因阿尔茨海默病小鼠模型，其中 CX3CR1 缺失。令人惊讶的是，CX3CR1 缺失导致 APPPS1 和 R1.40 两种 AD 小鼠模型中的β-淀粉样蛋白沉积呈基因剂量依赖性减少。免疫组织化学分析显示，CD68（小胶质细胞激活的标志物）的染色减少。此外，定量免疫组织化学分析显示，CX3CR1 缺失的 APPPS1 动物中，围绕β-淀粉样蛋白沉积的小胶质细胞数量减少。减少的β-淀粉样蛋白病理与 TNFα 和 CCL2 mRNA 水平降低，但 IL1β mRNA 水平升高相关，表明神经炎症环境发生改变。最后，为了解释这些看似矛盾的结果，体内和体外研究均提供了证据，表明 CX3CL1/CX3CR1 信号改变了小胶质细胞的吞噬能力，包括对 Aβ 纤维的摄取。综上所述，这些结果表明，神经元-小胶质细胞 fractalkine 信号的丧失会导致 AD 小鼠模型中β-淀粉样蛋白沉积减少，这可能是由 CX3CR1 缺失的小胶质细胞的激活和吞噬能力改变介导的。
