Microglia are active modulators of Alzheimer’s disease but their role in relation to amyloid plaques and synaptic changes due to rising amyloid beta is unclear. We add novel findings concerning these relationships and investigate which of our previously reported results from transgenic mice can be validated in knock-in mice, in which overexpression and other artefacts of transgenic technology are avoided. AppNL-F and AppNL-G-F knock-in mice expressing humanised amyloid beta with mutations in App that cause familial Alzheimer’s disease were compared to wild type mice throughout life. In vitro approaches were used to understand microglial alterations at the genetic and protein levels and synaptic function and plasticity in CA1 hippocampal neurones, each in relationship to both age and stage of amyloid beta pathology. The contribution of microglia to neuronal function was further investigated by ablating microglia with CSF1R inhibitor PLX5622. Both App knock-in lines showed increased glutamate release probability prior to detection of plaques. Consistent with results in transgenic mice, this persisted throughout life in AppNL-F mice but was not evident in AppNL-G-F with sparse plaques. Unlike transgenic mice, loss of spontaneous excitatory activity only occurred at the latest stages, while no change could be detected in spontaneous inhibitory synaptic transmission or magnitude of long-term potentiation. Also, in contrast to transgenic mice, the microglial response in both App knock-in lines was delayed until a moderate plaque load developed. Surviving PLX5266-depleted microglia tended to be CD68-positive. Partial microglial ablation led to aged but not young wild type animals mimicking the increased glutamate release probability in App knock-ins and exacerbated the App knock-in phenotype. Complete ablation was less effective in altering synaptic function, while neither treatment altered plaque load. Increased glutamate release probability is similar across knock-in and transgenic mouse models of Alzheimer’s disease, likely reflecting acute physiological effects of soluble amyloid beta. Microglia respond later to increased amyloid beta levels by proliferating and upregulating Cd68 and Trem2. Partial depletion of microglia suggests that, in wild type mice, alteration of surviving phagocytic microglia, rather than microglial loss, drives age-dependent effects on glutamate release that become exacerbated in Alzheimer’s disease.

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与阿尔茨海默病相关的敲入模型：突触传递、斑块和小胶质细胞的作用

小胶质细胞是阿尔茨海默病的活性调节剂，但它们与淀粉样蛋白斑块和由于β淀粉样蛋白升高引起的突触变化相关的作用尚不清楚。我们添加了关于这些关系的新发现，并研究了我们先前报道的转基因小鼠的哪些结果可以在敲入小鼠中得到验证，其中避免了转基因技术的过度表达和其他人工制品。将 AppNL-F 和 AppNL-GF 基因敲入小鼠与野生型小鼠进行比较，该小鼠表达人源化淀粉样蛋白β，其中 App 发生突变，导致家族性阿尔茨海默病。体外方法用于了解 CA1 海马神经元的遗传和蛋白质水平以及突触功能和可塑性的小胶质细胞变化，每一个都与年龄和淀粉样蛋白 β 病理学阶段有关。通过用 CSF1R 抑制剂 PLX5622 消融小胶质细胞，进一步研究了小胶质细胞对神经元功能的贡献。在检测到斑块之前，两个 App 敲入线都显示出增加的谷氨酸释放概率。与转基因小鼠的结果一致，这在 AppNL-F 小鼠的一生中持续存在，但在具有稀疏斑块的 AppNL-GF 中并不明显。与转基因小鼠不同，自发兴奋性活动的丧失仅发生在最后阶段，而自发抑制性突触传递或长期增强的幅度未检测到变化。此外，与转基因小鼠相比，两种 App 敲入系中的小胶质细胞反应都被延迟，直到出现适度的斑块负荷。存活的 PLX5266 耗尽的小胶质细胞往往是 CD68 阳性的。部分小胶质细胞消融导致老化但不是年轻的野生型动物模仿 App 敲入中增加的谷氨酸释放概率，并加剧了 App 敲入表型。完全消融在改变突触功能方面效果较差，而两种治疗都没有改变斑块负荷。增加的谷氨酸释放概率在阿尔茨海默病的敲入和转基因小鼠模型中相似，可能反映了可溶性淀粉样蛋白β的急性生理效应。小胶质细胞随后通过增殖和上调 Cd68 和 Trem2 对增加的淀粉样蛋白 β 水平作出反应。小胶质细胞的部分耗竭表明，在野生型小鼠中，存活的吞噬性小胶质细胞的改变，而不是小胶质细胞的损失，驱动了年龄依赖性对谷氨酸释放的影响，这种影响在阿尔茨海默病中变得更加严重。