A cellular approach to understanding and treating Gulf War Illness.
A cellular approach to understanding and treating Gulf War Illness.
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DOI：
10.1007/s00018-021-03942-3
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发表时间：
2021-11
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影响因子：
--
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--
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海湾战争病（GWI）是第一次海湾战争中约20万名退伍军人患的一种疾病，是由于接触低水平的有机磷农药和神经毒剂以及战场压力造成的。为了阐明GWI的脑相关症状的机制基础，将来自具有或不具有GWI的退伍军人的人诱导多能干细胞（hiPSC）分化成前脑神经元，然后暴露于由沙林类似物和皮质醇（一种人类应激激素）组成的海湾战争（GW）相关毒物方案。在暴露于毒物方案的神经元中观察到总tau和磷酸化tau水平升高、微管乙酰化减少、线粒体动力学/转运改变以及神经元活动减少。一些数据与一些退伍军人可能倾向于获得GWI的可能性一致。暴露于类似毒物方案的Wistar大鼠表现出轻度学习和记忆缺陷，以及海马CA 3区选择性的细胞丢失和tau病理学。这些细胞反应为患有GWI的退伍军人所遭受的记忆丧失提供了一种机制解释，并为这些退伍军人筛选药物和开发个性化疗法提供了一种基于细胞的模型。
Gulf War Illness (GWI), a disorder suffered by approximately 200,000 veterans of the first Gulf War, was caused by exposure to low-level organophosphate pesticides and nerve agents in combination with battlefield stress. To elucidate the mechanistic basis of the brain-related symptoms of GWI, human-induced pluripotent stem cells (hiPSCs) derived from veterans with or without GWI were differentiated into forebrain glutamatergic neurons and then exposed to a Gulf War (GW) relevant toxicant regimen consisting of a sarin analog and cortisol, a human stress hormone. Elevated levels of total and phosphorylated tau, reduced microtubule acetylation, altered mitochondrial dynamics/transport, and decreased neuronal activity were observed in neurons exposed to the toxicant regimen. Some of the data are consistent with the possibility that some veterans may have been predisposed to acquire GWI. Wistar rats exposed to a similar toxicant regimen showed a mild learning and memory deficit, as well as cell loss and tau pathology selectively in the CA3 region of the hippocampus. These cellular responses offer a mechanistic explanation for the memory loss suffered by veterans with GWI and provide a cell-based model for screening drugs and developing personalized therapies for these veterans.
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