Ultrastructural evidence of microglial heterogeneity in Alzheimer's disease amyloid pathology
Ultrastructural evidence of microglial heterogeneity in Alzheimer's disease amyloid pathology
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DOI：
10.1186/s12974-019-1473-9
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发表时间：
2019-04-16
影响因子：
9.3
通讯作者：
Tremblay, Marie-Eve
中科院分区：
文献类型：
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作者：
El Hajj, Hassan;Savage, Julie C.;Tremblay, Marie-Eve
背景：阿尔茨海默病（AD）是最常见的神经退行性疾病，其特征是细胞外纤维状淀粉样蛋白β（fAβ）的沉积和细胞内神经原纤维缠结的积累。随着 AD 的进展，Aβ 通过被小胶质细胞（大脑的免疫细胞）识别而驱动强烈且持久的炎症反应。小胶质细胞对 fA β 斑块的反应性可能会损害其正常的监视职责，促进突触丢失和神经元死亡，以及 AD 中的认知能力下降。 方法：在本研究中，我们进行了相关光、透射和扫描电子显微镜检查，以深入了解小胶质细胞的结构和功能异质性。我们分析了 14 个月大的 APP(Swe) -PS1 Delta e9 小鼠与野生型同窝小鼠的海马 CA1 区域中含有 fA β 斑块和神经元营养不良、仅营养不良或看起来健康的小胶质细胞体和过程。结果：我们的定量分析显示，AD 模型小鼠中的小胶质细胞体较大，并显示出细胞应激的超微结构迹象，尤其是附近的斑块。 AD 模型小鼠中小胶质细胞体和突起的吞噬能力总体较低。然而，它们含有增加的纤维状物质和靠近斑块的非空内含物。 AD 模型小鼠的小胶质细胞体和过程也显示出与含有碎片的细胞外空间袋的关联性减少。此外，与斑块相关的过程相比，AD模型小鼠健康亚区域的小胶质细胞过程更频繁地包围突触元件。这些在小鼠中的观察结果在两名 AD 患者（Braak 5 期）的死后海马样本中得到了定性复制。 结论： 总之，我们的研究结果在超微结构水平上鉴定了小鼠和人类常见的与淀粉样蛋白病理学相关的不同小胶质细胞转化。
Background: Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by the deposition of extracellular fibrillar amyloid beta (fA beta) and the intracellular accumulation of neurofibrillary tangles. As AD progresses, A beta drives a robust and prolonged inflammatory response via its recognition by microglia, the brain's immune cells. Microglial reactivity to fA beta plaques may impair their normal surveillance duties, facilitating synaptic loss and neuronal death, as well as cognitive decline in AD.Methods: In the current study, we performed correlative light, transmission, and scanning electron microscopy to provide insights into microglial structural and functional heterogeneity. We analyzed microglial cell bodies and processes in areas containing fA beta plaques and neuronal dystrophy, dystrophy only, or appearing healthy, among the hippocampus CA1 of 14-month-old APP(Swe) -PS1 Delta e9 mice versus wild-type littermates.Results: Our quantitative analysis revealed that microglial cell bodies in the AD model mice were larger and displayed ultrastructural signs of cellular stress, especially nearby plaques. Microglial cell bodies and processes were overall less phagocytic in AD model mice. However, they contained increased fibrillar materials and non-empty inclusions proximal to plaques. Microglial cell bodies and processes in AD model mice also displayed reduced association with extracellular space pockets that contained debris. In addition, microglial processes in healthy subregions of AD model mice encircled synaptic elements more often compared with plaque-associated processes. These observations in mice were qualitatively replicated in post-mortem hippocampal samples from two patients with AD (Braak stage 5).Conclusion: Together, our findings identify at the ultrastructural level distinct microglial transformations common to mouse and human in association with amyloid pathology.