Knock-in models related to Alzheimer's disease: synaptic transmission, plaques and the role of microglia.
Knock-in models related to Alzheimer's disease: synaptic transmission, plaques and the role of microglia.
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DOI：
10.1186/s13024-021-00457-0
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发表时间：
2021-07-15
影响因子：
15.1
通讯作者：
Cummings DM
中科院分区：
文献类型：
--
作者：
Benitez DP;Jiang S;Wood J;Wang R;Hall CM;Peerboom C;Wong N;Stringer KM;Vitanova KS;Smith VC;Joshi D;Saito T;Saido TC;Hardy J;Hanrieder J;De Strooper B;Salih DA;Tripathi T;Edwards FA;Cummings DM
小胶质细胞是阿尔茨海默氏病的活跃调节剂，但其与淀粉样蛋白斑块和由于β淀粉样蛋白升高导致的突触变化之间的作用尚不清楚。我们添加了有关这些关系的新发现，并研究了我们之前报道的转基因小鼠的哪些结果可以在基因敲入小鼠中得到验证，在敲入小鼠中避免了转基因技术的过度表达和其他人为因素。将表达人源化β淀粉样蛋白的AppNL-F和AppNL-G-F敲入小鼠与野生型小鼠进行比较，这些小鼠的App突变会导致家族性阿尔茨海默病。使用体外方法来了解小胶质细胞在遗传和蛋白质水平以及 CA1 海马神经元的突触功能和可塑性方面的变化，每种变化都与年龄和淀粉样蛋白病理学阶段有关。通过使用 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。两个应用程序敲入线都显示在检测噬菌斑之前谷氨酸释放概率增加。与转基因小鼠的结果一致，这种情况在 AppNL-F 小鼠的一生中持续存在，但在斑块稀疏的 AppNL-G-F 中并不明显。与转基因小鼠不同，自发兴奋活性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程度没有变化。此外，与转基因小鼠相比，两个 App 敲入系中的小胶质细胞反应均被延迟，直到出现中等的斑块负载。存活的 PLX5266 耗尽的小胶质细胞往往呈 CD68 阳性。部分小胶质细胞消融导致衰老而非年轻的野生型动物模仿 App 敲入中谷氨酸释放概率增加，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，而两种治疗都不能改变斑块负荷。阿尔茨海默病的敲入和转基因小鼠模型中谷氨酸释放概率的增加是相似的，这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 对淀粉样蛋白水平升高做出反应。小胶质细胞的部分耗尽表明，在野生型小鼠中，幸存的吞噬细胞小胶质细胞的改变，而不是小胶质细胞的损失，驱动了谷氨酸释放的年龄依赖性影响，这种影响在阿尔茨海默氏病中变得更加严重。在线版本包含可在 10.1186/s13024-021-00457-0 获取的补充材料。
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. The online version contains supplementary material available at 10.1186/s13024-021-00457-0.
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影响因子：
4.8
作者：
Forman, MS;Cook, DG;Lee, VMY
通讯作者：
Lee, VMY
影响因子：
16.2
作者：
Lee SH;Kang J;Ho A;Watanabe H;Bolshakov VY;Shen J
通讯作者：
Shen J
DOI：
10.1073/pnas.0600948103
发表时间：
2006-03-28
影响因子：
11.1
作者：
Jacobsen, JS;Wu, CC;Bloom, FE
通讯作者：
Bloom, FE
影响因子：
15.1
作者：
Clayton K;Delpech JC;Herron S;Iwahara N;Ericsson M;Saito T;Saido TC;Ikezu S;Ikezu T
通讯作者：
Ikezu T
影响因子：
25
作者：
D'Amelio, Marcello;Cavallucci, Virve;Cecconi, Francesco
通讯作者：
Cecconi, Francesco