Sepsis and the Systemic Cytokine Storm in Aging and Alzheimer Disease Models

摘要 严重的感染和败血症加速了美国老年人的认知能力下降，特别是那些早期的 阿尔茨海默病(AD)。已知脓毒症会引发全身性炎症性“细胞因子风暴”，这种风暴会随着 时间到了。然而，即使在患者感染缓解后，这种反应也经常持续。我们假设这是 系统性细胞因子风暴可能会影响有症状的AD患者和 没有已知认知缺陷的老年人。在临床前AD模型中，淀粉样蛋白和tau蛋白均增加 而病理学受全身炎症的影响。脓毒症患者的认知功能减退知之甚少 没有早期AD的幸存者，称为脓毒症相关性脑病(SAE)，以及这是否相关 与淀粉样蛋白和tau神经病理的发展有关。我们的主要假设是败血症和CCI导致 直接影响AD和SAE相关小鼠的独特局部和系统免疫反应 病理学。我们推测，在早期或前驱AD中，脓毒症会特别加剧大脑健康。 通过加重淀粉样蛋白和tau蛋白的神经病理，而在认知正常的老年人中，SAE结果 会因老化的途径而加剧。我们将使用4个具体目标来检验这些假设。在目标1中，我们将 评估年龄是否在导致脓毒症引起的神经退行性变和认知丧失中起关键作用 (SAE)野生型小鼠。在这里，我们建议采用一种存活的盲肠结扎和穿孔模型 多菌败血症与每日慢性应激(CLP+DC)在6月龄(Mo)和18月龄成人中的应用C57BL/6 (B6)混合性别小鼠。小鼠将在脓毒症后4或8周因炎症和神经病理而被安乐死。 评估，其中将包括分析神经元死亡和脑部炎症变化。同步空间 转录和蛋白质组学分析(NanoStringGeoMx™)将允许对特定脑区进行评估 对外周细胞因子风暴的反应变化。将分析血浆中的炎性细胞因子和 精选的警员。小鼠在遭受败血症侮辱后也将接受认知评估。在目标2)中，我们将 评估CLP+DCs诱导的全身性炎症是否改变Aβ沉积。在这里，我们将使用两个应用程序 转基因小鼠模型--进展快的TgCRND8小鼠和进展缓慢的Tg.PrP huaβ(APPsi)小鼠 小鼠--评估系统性细胞因子风暴如何调节淀粉样蛋白沉积。在目标3)中，我们将评估 全身性炎症加重了tau的病理。我们将评估脓毒症是否导致AD-tau病理- PS19小鼠的相关脑区。最后，在目标4)中，我们将测试预防性操作是否 免疫系统在选定的动物模型中改变SAE或AD相关的病理。使用AAV定向 诱饵sIL-10R，我们将测试系统性或在大脑中抑制IL-10是否会减弱 神经病理/行为结果。更多的小鼠将在脓毒症期间口服二甲双胍 具有神经保护作用。这项研究将为脓毒症引起的病理提供一个机制上的理解以及 患有和不患有AD的老年人之间的差异。

ABSTRACT Severe infection and sepsis accelerate cognitive decline in older Americans, especially those with incipient Alzheimer's disease (AD). Sepsis is known to induce a systemic inflammatory `cytokine storm', which wanes with time. However, this response often persists even after infection resolution in patients. We hypothesize that this systemic cytokine storm can potentially affect brain neuropathology in both pre-symptomatic AD patients and in older adults with no known cognitive deficits. In preclinical AD models, both amyloid and tau protein accretion and pathology are influenced by systemic inflammation. Less is known about the cognitive decline in sepsis survivors without incipient AD, known as sepsis-associated encephalopathy (SAE), and whether this is related to development of amyloid and tau neuropathology. Our overarching hypothesis is that sepsis and CCI induce unique local and systemic immunological responses that directly influence murine AD- and SAE-related pathology. We hypothesize that in incipient or prodromal AD, sepsis would specifically exacerbate brain health by exacerbating amyloid and tau neuropathology, while in cognitively normal older individuals, SAE outcomes would be exacerbated by aging pathways. We will test these hypotheses using 4 specific aims. In Aim 1) we will evaluate whether age plays a critical role in driving sepsis-induced neurodegeneration and loss of cognition (SAE) in wild-type mice. Here we propose to employ a survivable cecal ligation and puncture model of polymicrobial sepsis with daily chronic stress (CLP+DCS) in 6 month (mo) young and 18 mo older adult C57BL/6 (B6) mixed sex mice. Mice will be euthanized at 4 or 8 weeks post-sepsis for inflammatory and neuropathologic evaluation, which will include analysis of neuronal death, and brain inflammatory changes. Simultaneous spatial transcriptomic and proteomic profiling (NanoString GeoMx™) will allow assessment of brain region-specific alterations in response to the peripheral cytokine storm. Plasma will be analyzed for inflammatory cytokines and selected alarmins. Mice will also undergo cognitive assessment following their septic insult. In Aim 2) we will evaluate whether CLP+DCS-induced systemic inflammation alters Aβ deposition. Here we will use two APP transgenic mouse models – the fast progressing TgCRND8 mice and the slow progressing Tg.PrP HuAβ (APPsi) mice - to assess how systemic cytokine storm modulates amyloid deposition. In Aim 3) we will evaluate whether systemic inflammation exacerbates tau pathology. We will assess whether sepsis induces tau pathology in AD- relevant brain areas in the PS19 mice. Finally, in Aim 4) we will test whether prophylactic manipulation of the immune system alters SAE or AD-associated pathologies in selected animal models. Using an AAV-directed decoy sIL-10R, we will test whether suppressing IL-10 systemically or in the brain attenuates neuropathologic/behavioral outcomes. Additional mice will receive metformin orally during sepsis as it may be neuroprotective. This study will provide a mechanistic under-standing of sepsis-induced pathology, as well as differences in older adults with and without pre-existing AD.