Enduring Changes in Neuronal Function upon Systemic Inflammation Are NLRP3 Inflammasome Dependent
Enduring Changes in Neuronal Function upon Systemic Inflammation Are NLRP3 Inflammasome Dependent
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DOI：
10.1523/jneurosci.0200-20.2020
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发表时间：
2020-07-08
影响因子：
5.3
通讯作者：
Korte, Martin
中科院分区：
文献类型：
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作者：
Beyer, Marianna M. S.;Lonnemann, Niklas;Korte, Martin
神经炎症可由对大脑的各种损伤引起，是包括阿尔茨海默病（AD）在内的神经退行性疾病的重要病理标志。感染引发的急性全身性炎症能够诱导神经炎症，并可能对神经元形态、突触可塑性和认知功能产生负面影响。与急性效应相反，系统性免疫刺激对大脑的持续影响在很大程度上仍未被探索。在这里，我们报告了野生型（WT）小鼠对鼠伤寒沙门氏菌脂多糖（LPS）的系统性免疫刺激的年龄依赖性脆弱性。外周免疫刺激后3个月神经元复杂性下降，并伴有长期增强（LTP）和空间学习功能的损害。衰老的APP/PS1小鼠对大肠杆菌脂多糖的敏感性也增加，而对WT小鼠没有影响。我们进一步报道，这些作用是由nod样受体家族，pyrin结构域3 （NLRP3）炎性体激活介导的，因为NLRP3抑制剂MCC950的遗传消融和药理抑制可以挽救形态学和电生理表型。
Neuroinflammation can be caused by various insults to the brain and represents an important pathologic hallmark of neurodegenerative diseases including Alzheimer's disease (AD). Infection-triggered acute systemic inflammation is able to induce neuroinflammation and may negatively affect neuronal morphology, synaptic plasticity, and cognitive function. In contrast to acute effects, persisting consequences for the brain on systemic immune stimulation remain largely unexplored. Here, we report an age-dependent vulnerability of wild-type (WT) mice of either sex toward a systemic immune stimulation by Salmonella typhimurium lipopolysaccharide (LPS). Decreased neuronal complexity three months after peripheral immune stimulation is accompanied by impairment in long-term potentiation (LTP) and spatial learning. Aged APP/PS1 mice reveal an increased sensitivity also to LPS of Escherichia coli, which had no effect in WT mice. We further report that these effects are mediated by NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation, since the genetic ablation and pharmacological inhibition using the NLRP3 inhibitor MCC950 rescue the morphological and electrophysiological phenotype.