Mitochondria-Targeted Human Catalase in the Mouse Longevity MCAT Model Mitigates Head-Tilt Bedrest-Induced Neuro-Inflammation in the Hippocampus.
Mitochondria-Targeted Human Catalase in the Mouse Longevity MCAT Model Mitigates Head-Tilt Bedrest-Induced Neuro-Inflammation in the Hippocampus.
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DOI：
10.3390/life12111838
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发表时间：
2022-11-09
期刊：
影响因子：
--
通讯作者：
Allen AR
中科院分区：
文献类型：
--
作者：
Rubinstein L;Kiffer F;Puukila S;Lowe MG;Goo B;Luthens A;Schreurs AS;Torres SM;Steczina S;Tahimic CGT;Allen AR
在长时间航天飞行期间经历的微重力（以头倾斜卧床和后肢卸载为模型）会导致神经系统后果、中枢神经系统功能障碍，并在执行关键任务期间可能造成损害。在地球上的卧床休息、久坐不动的生活方式和肌肉废用中也观察到类似的病理。在我们之前的研究中，我们看到头部倾斜卧床与社会隔离一起上调海马体和血浆中促炎细胞因子的环境。这些变化在线粒体中过表达人过氧化氢酶的MCAT小鼠模型中得到缓解，指出了ROS信号在这种应激反应中的重要性。在这里，我们使用了一个头部倾斜模型在社会圈养的小鼠梳理出头部倾斜卧床不隔离的影响。为了找到引起细胞因子反应的潜在分子机制，我们测量了海马中小胶质细胞活化的指标CD 68以及正常笼内行为的变化。我们假设后肢卸载（HU）将引起小胶质细胞海马激活，这将在MCAT ROS淬灭小鼠模型中得到缓解。事实上，我们看到海马中HU后活化的小胶质细胞CD 68标记物升高，并且这种病理在MCAT小鼠中减轻。此外，我们还鉴定了海马中的细胞因子，它们与CD 68呈显著正相关，与探索行为呈负相关，表明神经炎症与行为后果之间存在联系。揭示分子和行为变化之间的相关性可以揭示指示这些反应的生物标志物，也可以为长期太空任务和/或地球上肌肉废用后的认知变化的治疗和预防提供潜在目标。
Microgravity (modeled by head-tilt bedrest and hind-limb unloading), experienced during prolonged spaceflight, results in neurological consequences, central nervous system (CNS) dysfunction, and potentially impairment during the performance of critical tasks. Similar pathologies are observed in bedrest, sedentary lifestyle, and muscle disuse on Earth. In our previous study, we saw that head-tilt bedrest together with social isolation upregulated the milieu of pro-inflammatory cytokines in the hippocampus and plasma. These changes were mitigated in a MCAT mouse model overexpressing human catalase in the mitochondria, pointing out the importance of ROS signaling in this stress response. Here, we used a head-tilt model in socially housed mice to tease out the effects of head-tilt bedrest without isolation. In order to find the underlying molecular mechanisms that provoked the cytokine response, we measured CD68, an indicator of microglial activation in the hippocampus, as well as changes in normal in-cage behavior. We hypothesized that hindlimb unloading (HU) will elicit microglial hippocampal activations, which will be mitigated in the MCAT ROS-quenching mice model. Indeed, we saw an elevation of the activated microglia CD68 marker following HU in the hippocampus, and this pathology was mitigated in MCAT mice. Additionally, we identified cytokines in the hippocampus, which had significant positive correlations with CD68 and negative correlations with exploratory behaviors, indicating a link between neuroinflammation and behavioral consequences. Unveiling a correlation between molecular and behavioral changes could reveal a biomarker indicative of these responses and could also result in a potential target for the treatment and prevention of cognitive changes following long space missions and/or muscle disuse on Earth.
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影响因子：
2
作者：
Frigeri, Antonio;Iacobas, Dumitru A.;Iacobas, Sanda;Nicchia, Grazia Paola;Desaphy, Jean Francois;Camerino, Diana Conte;Svelto, Maria;Spray, David C.
通讯作者：
Spray, David C.
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作者：
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影响因子：
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Sams C
影响因子：
24.1
作者：
Hoff, Paula;Belavy, Daniel L.;Buttgereit, Frank
通讯作者：
Buttgereit, Frank