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

衰老和阿尔茨海默病模型中的脓毒症和系统性细胞因子风暴

基本信息

批准号：
10513525
负责人：
PARAMITA CHAKRABARTY
金额：
$ 221.84万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2025-07-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10513525
关键词：
Admission activity Affect Age Age-Months Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia American Amyloid Amyloid Proteins Amyloid beta-Protein Amyloid deposition Anatomy Animal Model Area Attenuated Automobile Driving Behavior Blood Blood - brain barrier anatomy Brain Brain region Chronic stress Clinical Cognition Cognitive Cognitive deficits Deposition Development Diagnosis Diffuse Discipline Elderly Encephalopathies Etiology Evaluation Functional disorder Genetic Genomics Goals Harvest Health Immune response Immune system Immunologic Factors Immunologist Impaired cognition Impairment Individual Infection Inflammation Inflammatory Inflammatory Response Interdisciplinary Study Interleukin-10 Label Leukocytes Life Metformin Modeling Mouse Strains Mus Nerve Degeneration Neurocognitive Neurons Oral Organ Outcome Paralysed Pathologic Pathologist Pathology Pathway interactions Patients Peripheral Pharmacology Plasma Play Population Postoperative Period PrP Proteomics Research Resolution Role Secondary to Sepsis Survivors Tauopathies Testing Time Transgenic Mice Wild Type Mouse abeta deposition adverse outcome age effect base behavioral outcome brain health cecal ligation puncture clinically relevant cognitive testing cohort cytokine cytokine release syndrome design hyperphosphorylated tau middle age mouse model nano-string neurobehavior neurobehavioral neuroinflammation neuron loss neuropathology novel polymicrobial sepsis pre-clinical prodromal Alzheimer&apos s disease prophylactic resilience response septic sex synergism systemic inflammatory response tau Proteins transcriptomics

项目摘要

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.

抽象的老年人的严重感染和败血症会加速认知能力下降，尤其是那些初期的人阿尔茨海默氏病（AD）。已知败血症会诱导全身性炎症性“细胞因子风暴”，随着时间。但是，即使患者感染了感染后，这种反应也常常仍然存在。我们假设这是全身细胞因子风暴可能会影响症状前AD患者的脑神经病理学以及没有已知认知缺陷的老年人。在临床前广告模型中，淀粉样蛋白和tau蛋白增生病理和病理受系统性炎症的影响。对败血症的认知下降知之甚少没有初期AD的幸存者，称为败血症相关的脑病（SAE），以及这是否相关发展淀粉样蛋白和TAU神经病理学。我们的总体假设是败血症和CCI影响独特的局部和系统性免疫反应，直接影响鼠类和SAE相关的鼠类AD和SAE 病理。我们假设在初期或前驱AD中，败血症会特别加剧大脑健康通过加剧淀粉样蛋白和tau神经病理学，而在认知正常的老年人中，SAE的结果老化途径会加剧。我们将使用4个特定目标来检验这些假设。在目标1）我们将评估年龄在驱动败血症引起的神经变性和认知丧失方面起着关键作用（SAE）在野生型小鼠中。在这里，我们建议采用可生存的盲肠结扎和穿刺模型在6个月（MO）和18 mo老年人C57BL/6的每日慢性应激（CLP+DC）的多数败血症（CLP+DC）（B6）混合性小鼠。小鼠将在sepsis后4或8周安乐死，以进行炎症和神经病理学评估将包括分析神经元死亡和脑部炎症性变化。同时空间转录组和蛋白质组学分析（Nanostring GEOMX™）将允许评估大脑区域特异性响应周围细胞因子风暴的改变。血浆将分析炎症细胞因子和选定的警报。小鼠在化粪池侮辱后还将接受认知评估。在目标2）我们将评估CLP+DCS诱导的全身注入是否改变了Aβ沉积。在这里，我们将使用两个应用转基因小鼠模型 - 快速进展的TGCRND8小鼠和缓慢的TG.PRPHUAβ（APPSI）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）我们将评估是否系统性炎症加剧了tau病理学。我们将评估败血症是否诱导tau病理学 PS19小鼠的相关大脑区域。最后，在AIM 4）我们将测试是否对免疫系统在选定的动物模型中改变了SAE或与AD相关的病理。使用AAV指导诱饵SIL-10R，我们将测试是系统地抑制IL-10还是在大脑中抑制神经病理/行为结果。在败血症期间，其他小鼠会口服二甲双胍，因为它可能是神经保护性。这项研究将对败血症诱导的病理学以及具有和没有预先存在AD的老年人的差异。