Chronic cerebral lipocalin 2 exposure elicits hippocampal neuronal dysfunction and cognitive impairment.
Chronic cerebral lipocalin 2 exposure elicits hippocampal neuronal dysfunction and cognitive impairment.
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DOI：
10.1016/j.bbi.2021.07.002
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Marks DL
中科院分区：
文献类型：
--
作者：
Olson B;Zhu X;Norgard MA;Diba P;Levasseur PR;Buenafe AC;Huisman C;Burfeind KG;Michaelis KA;Kong G;Braun T;Marks DL
脂质运载蛋白2（LCN 2）是一种多效性分子，在中枢神经系统（CNS）的几种急性和慢性病理中被诱导。LCN 2的急性诱导作为一个有益的过程而发展，旨在通过从病原体中螯合铁来对抗细菌感染，而LCN 2在慢性非感染性疾病中的作用仍不清楚，最近的研究表明LCN 2具有神经毒性。然而，LCN 2是否足以诱导行为和认知改变仍不清楚。在本文中，我们试图解决大脑LCN 2在急性和慢性环境中对认知的作用。我们证明了LCN 2在急性和慢性炎症条件下（包括基于LPS的脓毒症和癌症恶病质）在CNS中被强烈诱导。在体内，LPS激发导致中枢神经系统中LCN 2的全面诱导，而癌症恶病质导致血管系统特异性分布。与这些体内观察结果相似，体外建模表明，当用LPS攻击时，胶质细胞和脑内皮细胞都产生并分泌LCN 2，而当用癌症条件培养基攻击时，只有脑内皮细胞分泌LCN 2。慢性而非短期的脑LCN 2暴露导致海马神经元染色强度降低、新生神经元增加、小胶质细胞活化和CNS免疫细胞浸润增加，而基因集分析表明这些效应是通过黑皮质素-4受体非依赖性机制介导的。原代海马神经元的RNA测序分析揭示了与长时间LCN 2暴露相关的不同转录组，本体分析提示神经突生长改变和空间学习异常。事实上，LCN 2处理的海马神经元显示出钝的神经突过程，并且暴露于长时间脑LCN 2水平的小鼠经历了空间参考记忆的减少，如Y-迷宫评估所示。这些发现暗示LCN 2是慢性疾病背景下认知下降的病理介质。
Lipocalin 2 (LCN2) is a pleiotropic molecule that is induced in the central nervous system (CNS) in several acute and chronic pathologies. The acute induction of LCN2 evolved as a beneficial process, aimed at combating bacterial infection through the sequestration of iron from pathogens, while the role of LCN2 during chronic, non-infectious disease remains unclear, and recent studies suggest that LCN2 is neurotoxic. However, whether LCN2 is sufficient to induce behavioral and cognitive alterations remains unclear. In this paper, we sought to address the role of cerebral LCN2 on cognition in both acute and chronic settings. We demonstrate that LCN2 is robustly induced in the CNS during both acute and chronic inflammatory conditions, including LPS-based sepsis and cancer cachexia. In vivo, LPS challenge results in a global induction of LCN2 in the central nervous system, while cancer cachexia results in a distribution specific to the vasculature. Similar to these in vivo observations, in vitro modeling demonstrated that both glia and cerebral endothelium produce and secrete LCN2 when challenged with LPS, while only cerebral endothelium secrete LCN2 when challenged with cancer-conditioned medium. Chronic, but not short-term, cerebral LCN2 exposure resulted in reduced hippocampal neuron staining intensity, an increase in newborn neurons, microglial activation, and increased CNS immune cell infiltration, while gene set analyses suggested these effects were mediated through melanocortin-4 receptor independent mechanisms. RNA sequencing analyses of primary hippocampal neurons revealed a distinct transcriptome associated with prolonged LCN2 exposure, and ontology analysis was suggestive of altered neurite growth and abnormal spatial learning. Indeed, LCN2-treated hippocampal neurons display blunted neurite processes, and mice exposed to prolonged cerebral LCN2 levels experienced a reduction in spatial reference memory as indicated by Y-maze assessment. These findings implicate LCN2 as a pathologic mediator of cognitive decline in the setting of chronic disease.
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影响因子：
25
作者：
Gan L;Cookson MR;Petrucelli L;La Spada AR
通讯作者：
La Spada AR
炎症诱导的嗜睡是通过抑制Orexin神经元活性介导的。
DOI：
10.1523/jneurosci.2311-11.2011
发表时间：
2011-08-03
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
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通讯作者：
Marks DL
DOI：
10.1016/j.bbi.2018.05.021
发表时间：
2018-10
期刊：
Brain, behavior, and immunity
影响因子：
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作者：
Burfeind KG;Zhu X;Levasseur PR;Michaelis KA;Norgard MA;Marks DL
通讯作者：
Marks DL
影响因子：
8.1
作者：
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影响因子：
3.5
作者：
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