Department of Applied Biology, Kyoto Institute of Technology, Saga Campus, Saga Ippongi-cho, Ukyo-ku, Kyoto 616-8354, Japan; Department of Drosophila Genomics and Genetic Resources, Center for Advanced Insect Research Promotion, Kyoto Institute of Technology, Saga Ippongi-cho, Ukyo-ku, Kyoto 616-8354, Japan.
Department of Applied Biology, Kyoto Institute of Technology, Saga Campus, Saga Ippongi-cho, Ukyo-ku, Kyoto 616-8354, Japan.
Brain Behav Immun. 2019 Aug;80:427-438. doi: 10.1016/j.bbi.2019.04.023. Epub 2019 Apr 12.
Symptoms of many neurodegenerative diseases appear later in human life. However, young animal models for penetrating traumatic brain injury (pTBI) have been used to study neurodegenerative diseases and evaluate the efficacy of neuroprotective medicines. Possibly because of this discordance, effective neuroprotective drugs have still not been developed. For patients suffering from pTBI, aging is known to be a significant prognostic factor of mortality. In this study, we aimed to establish a model of aged pTBI animals using Drosophila melanogaster. We successfully generated aged pTBI flies as a new pTBI model showing increased neurodegeneration and higher mortality. To elucidate the mechanism of increased vulnerability in aged pTBI animals, we analyzed the GenBank-deposited transcriptome data of young and aged flies, demonstrating the importance of innate immunity genes for higher mortality in aged pTBI models. We found that in the context of pTBI, normal aging strongly activated the expression of antimicrobial peptide genes and upregulated the nuclear factor-κB gene in the immune deficiency pathway, but not the Toll pathway. Moreover, we found that minocycline increased the survival of young pTBI flies, but not aged pTBI flies. These results suggested that immune system activation under neurodegenerative conditions was involved in normal aging, thereby inhibiting the medicinal efficacy of neuroprotective drugs effective for young flies in aged flies.
许多神经退行性疾病的症状出现在人类生命的后期。然而，穿透性创伤性脑损伤 (pTBI) 的年轻动物模型已被用于研究神经退行性疾病和评估神经保护药物的疗效。可能由于这种差异，有效的神经保护药物仍未开发出来。对于患有 pTBI 的患者，衰老被认为是死亡率的一个重要预后因素。在这项研究中，我们旨在使用黑腹果蝇建立老年 pTBI 动物模型。我们成功地生成了老年 pTBI 果蝇，作为一种新的 pTBI 模型，表现出更高的神经退行性和更高的死亡率。为了阐明老年 pTBI 动物易损性增加的机制，我们分析了年轻和老年果蝇的 GenBank 转录组数据，表明先天免疫基因对老年 pTBI 模型中更高死亡率的重要性。我们发现，在 pTBI 的情况下，正常衰老强烈激活了抗菌肽基因的表达，并上调了免疫缺陷途径中的核因子-κB 基因，而不是 Toll 途径。此外，我们发现米诺环素增加了年轻 pTBI 果蝇的存活率，但不能增加老年 pTBI 果蝇的存活率。这些结果表明，神经退行性条件下的免疫系统激活参与了正常衰老，从而抑制了对年轻果蝇有效的神经保护药物在老年果蝇中的药效。
