流感病毒感染会加剧老年小鼠大脑中与神经认知功能障碍有关的基因表达。

IF 5.2 2区 医学 Q1 GERIATRICS & GERONTOLOGY
Wenxin Wu, Jeremy S Alexander, J Leland Booth, Craig A Miller, Jordan P Metcalf, Douglas A Drevets
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引用次数: 0

摘要

背景:年龄大于 65 岁是人类感染流感后出现不良后果的关键风险因素。具体而言,除呼吸系统疾病外,非神经性甲型流感病毒(IAV)还会导致神经认知并发症,如新发抑郁症,并增加住院后痴呆的风险。本研究旨在通过确定非神经性甲型流感病毒感染小鼠模型中年轻小鼠和年老小鼠大脑基因表达的差异,找出这些影响的潜在机制:年轻(12 周)和年老(70 周)的 C57Bl/6J 小鼠经鼻接种 200 PFU H1N1 A/PR/34/8 (PR8) 或无菌 PBS(模拟)。通过 qRT-PCR 检测肺部和脑部的基因表达,并与β-肌动蛋白进行归一化。研究结果由 nCounter Mouse Neuroinflammation Array(NanoString)确认,并用 nSolver 4.0 和 Ingenuity Pathway Analysis(IPA,Qiagen)进行分析:结果:IAV PR8没有侵入中枢神经系统。年轻小鼠和年老小鼠在基线和非神经性 IAV 感染期间的脑部基因表达有显著差异。基因阵列显示,感染后3天,老龄小鼠表观遗传调控、胰岛素信号和神经元与神经传导通路下调,而同一时间点,年轻小鼠的这些通路没有变化或诱导。IPA显示了老年小鼠和年轻小鼠之间明显的基线差异。在 IAV 感染期间,老年小鼠与认知障碍、记忆缺陷和学习相关的基因表达比年轻小鼠更差。通过IPA分析,老年小鼠与记忆丧失和认知功能障碍相关的基因表达发生了更严重的变化:这些数据表明,与学习和认知能力相关的基因和通路在基线时在老年小鼠中表现较差,但在感染 IAV 后进一步恶化,这与老年患者的情况类似。IAV感染引发的大脑早期事件预示着老年神经认知病理学的下游发展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Influenza virus infection exacerbates gene expression related to neurocognitive dysfunction in brains of old mice.

Background: Age > 65 years is a key risk factor for poor outcomes after human influenza infection. Specifically, in addition to respiratory disease, non-neurotropic influenza A virus (IAV) causes neuro-cognitive complications, e.g. new onset depression and increases the risk of dementia after hospitalization. This study aimed to identify potential mechanisms of these effects by determining differences between young and old mice in brain gene expression in a mouse model of non-neurotropic IAV infection.

Methods: Young (12 weeks) and old (70 weeks) C57Bl/6J mice were inoculated intranasally with 200 PFU H1N1 A/PR/34/8 (PR8) or sterile PBS (mock). Gene expression in lung and brain was measured by qRT-PCR and normalized to β-actin. Findings were confirmed using the nCounter Mouse Neuroinflammation Array (NanoString) and analyzed with nSolver 4.0 and Ingenuity Pathway Analysis (IPA, Qiagen).

Results: IAV PR8 did not invade the central nervous system. Young and old mice differed significantly in brain gene expression at baseline and during non-neurotropic IAV infection. Expression of brain Ifnl, Irf7, and Tnf mRNAs was upregulated over baseline control at 3 days post-infection (p.i.) only in young mice, but old mice expressed more Ifnl than young mice 7 days p.i. Gene arrays showed down-regulation of the Epigenetic Regulation, Insulin Signaling, and Neurons and Neurotransmission pathways in old mice 3 days p.i. while young mice demonstrated no change or induction of these pathways at the same time point. IPA revealed marked baseline differences between old and young mice. Gene expression related to Cognitive Impairment, Memory Deficits and Learning worsened in old mice relative to young mice during IAV infection. Aged mice demonstrate more severe changes in gene expression related to memory loss and cognitive dysfunction by IPA.

Conclusions: These data suggest the genes and pathways related to learning and cognitive performance that were worse at baseline in old mice were further worsened by IAV infection, similar to old patients. Early events in the brain triggered by IAV infection portend downstream neurocognitive pathology in old adults.

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来源期刊
Immunity & Ageing
Immunity & Ageing GERIATRICS & GERONTOLOGY-IMMUNOLOGY
CiteScore
10.20
自引率
3.80%
发文量
55
期刊介绍: Immunity & Ageing is a specialist open access journal that was first published in 2004. The journal focuses on the impact of ageing on immune systems, the influence of aged immune systems on organismal well-being and longevity, age-associated diseases with immune etiology, and potential immune interventions to increase health span. All articles published in Immunity & Ageing are indexed in the following databases: Biological Abstracts, BIOSIS, CAS, Citebase, DOAJ, Embase, Google Scholar, Journal Citation Reports/Science Edition, OAIster, PubMed, PubMed Central, Science Citation Index Expanded, SCImago, Scopus, SOCOLAR, and Zetoc.
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