Cognitive effects of the GSK-3 inhibitor ?lithium? in LPS/chronic mild stress rat model of depression: Hippocampal and cortical neuroinflammation and tauopathy
Cognitive effects of the GSK-3 inhibitor ?lithium? in LPS/chronic mild stress rat model of depression: Hippocampal and cortical neuroinflammation and tauopathy
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DOI：
10.1016/j.neuro.2020.12.016
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发表时间：
2021-01-11
期刊：
影响因子：
3.4
通讯作者：
Abdel-Tawab, Ahmed M.
中科院分区：
文献类型：
--
作者：
Ebeid, Mai A.;Habib, Mohamed Z.;Abdel-Tawab, Ahmed M.
低剂量重复内毒素激发后慢性轻度应激(LPS/CMS)方案已被引入作为结合免疫激活和慢性心理应激作用的抑郁啮齿动物模型。然而，到目前为止，这一范式对认知功能的影响还没有被研究。方法：本研究使用锂(Li)作为GSK-3抑制的工具，评估了内毒素/CMS诱导的认知效应以及糖原合成酶-38(GSK-38)的激活以及随后的神经炎症和病理tau沉积在这些效应的发病机制中的作用。结果：LPs预激发减少了CMS诱导的神经炎症、抑郁样行为和认知灵活性。它还改善了空间学习，但增加了GSK-38的表达，并夸大了过度磷酸化的tau在海马区和前额叶皮质的积聚。LI可改善CMS和LPS/CMS诱导的抑郁和认知障碍，减少GSK-38的过度表达和tau的过度磷酸化，阻止神经炎症，提高神经元存活率。结论：本研究引起了人们对LPS/CMS引发的认知变化的关注，并强调了先前的低剂量免疫攻击如何发展了一种适应能力，以缓冲炎症损伤和维持抵御威胁所需的认知能力。这项工作还强调了LI(作为GSK38抑制剂)在阻止夸大的脊椎病和神经炎症、挽救神经元存活和保护认知功能方面的有利作用。然而，需要利用不同的低剂量内毒素激发程序进行进一步的深入研究，以阐明免疫激活和慢性应激暴露之间的复杂相互作用。
Low-dose repeated lipopolysaccharide pre-challenge followed by chronic mild stress (LPS/CMS) protocol has been introduced as a rodent model of depression combining the roles of immune activation and chronic psychological stress. However, the impact of this paradigm on cognitive functioning has not been investigated hitherto.Methods: This study evaluated LPS/CMS-induced cognitive effects and the role of glycogen synthase kinase-38 (GSK-38) activation with subsequent neuroinflammation and pathological tau deposition in the pathogenesis of these effects using lithium (Li) as a tool for GSK-3 inhibition.Results: LPS pre-challenge reduced CMS-induced neuroinflammation, depressive-like behavior and cognitive inflexibility. It also improved spatial learning but increased GSK-38 expression and exaggerated hyperphosphorylated tau accumulation in hippocampus and prefrontal cortex. Li ameliorated CMS and LPS/CMSinduced depressive and cognitive deficits, reduced GSK-38 over-expression and tau hyperphosphorylation, impeded neuroinflammation and enhanced neuronal survival.Conclusion: This study draws attention to LPS/CMS-triggered cognitive changes and highlights how prior lowdose immune challenge could develop an adaptive capacity to buffer inflammatory damage and maintain the cognitive abilities necessary to withstand threats. This work also underscores the favorable effect of Li (as a GSK38 inhibitor) in impeding exaggerated tauopathy and neuroinflammation, rescuing neuronal survival and preserving cognitive functions. Yet, further in-depth studies utilizing different low-dose LPS challenge schedules are needed to elucidate the complex interactions between immune activation and chronic stress exposure.