Influence of systemic immune inflammation upon the tauopathy phenotype in mouse models

全身免疫炎症对小鼠模型tau蛋白病表型的影响

• 批准号: 9592680
• 负责人: David Morgan
• 金额: $ 41.82万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-11-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9592680
• 关键词: Influence; systemic; immune; inflammation; upon

 DESCRIPTION (provided by applicant): This project is in response to RFA "Immune and Inflammatory Mechanisms in AD". A consortium of investigators with expertise in mouse models, behavior, surgery, histopathology, neurochemistry, immunology, brain aging and Alzheimer's disease have been assembled to approach the problem of systemic immune system influences on the development of AD pathology, specifically tau deposition. Two major questions are addressed. The first question regards the role of physiological aging in the nervous system, the cellular/humoral circulation or both in regulating the accumulation of tau pathology or modulating its impact upon the CNS. We plan to discern the relative contribution of CNS versus systemic influences by attempting to rejuvenate or senesce the systemic circulation and monitor the impact upon the tau phenotype in the brain of young and old mice. Our preliminary data indicate that even by middle age mice have enhanced sensitivity to tau over- expression, with accumulation of pathology when tauopathy is initiated at 11 mo, but not at 4 mo. The second question regards the influence of immunostimulants as sterile mimetics of different types of infections. Lipopolysaccharide will be used as a prototype, but immunostimulants mimicking viral and fungal infections will also be examined. An extensive human literature indicates that infections or trauma resulting in delirium increase risk of AD and accelerate the course of cognitive decline. We further expect these immunostimulants will exacerbate the tau pathology, and synergize with the age of the mice. Finally, we will seek to counter the impacts of age or innate immunostimulants by reversing the effects of aging on specific proteins in the circulation. This is based on recent work by others that indicate the rejuvenating effects of parabiosis can be replicated by supplementation with a single protein shown to decline during aging. Other work shows the senescing effects of parabiosis can be replicated by another individual protein that increases with age. We will discover additional candidate proteins through proteomic analysis of plasma protein responses to age and immunostimulant treatment. Success in these aims will provide candidate targets to be explored for intervention in individuals with delirium to make the cognitive decline reversible, as in younger individuals, rather than contributing to the onset or progression of dementia.

 描述（由应用程序提供）：该项目是对RFA“ AD中的免疫和炎症机制”的响应。已经组装了一个在小鼠模型，行为，手术，组织病理学，组织病理学，神经化学，脑老化和阿尔茨海默氏病的研究人员的联盟中，以解决系统免疫系统系统对AD病理学发展的影响，特别是TAU证词的影响。解决了两个主要问题。第一个问题涉及身体衰老在神经系统，细胞/体液循环中的作用，或者在调节Tau病理学或调节其对CNS的影响中的作用。我们计划通过试图使系统循环恢复或感官来辨别中枢神经系统与全身影响的相对贡献，并监测对年龄和老鼠大脑中TAU表型的影响。我们的初步数据表明，即使是中年小鼠对Tau过表达的敏感性增强，当tauopathy在11 mo下启动时，病理学的声音也具有病理学的声音，但在4个月中却没有。第二个问题涉及免疫刺激剂作为不同类型感染的无菌模拟物的影响。脂多糖将被用作原型，但是还将检查模仿病毒和真菌感染的免疫刺激剂。广泛的人类文献表明，导致ir妄的感染或创伤增加了AD的风险，并加速了认知能力下降的过程。我们进一步期望这些免疫刺激剂会加剧tau病理，并与小鼠的年龄协同作用。最后，我们将寻求通过逆转衰老对循环中特定蛋白的影响来应对年龄或先天免疫刺激物的影响。这是基于其他人的最新工作，表明可以通过补充显示在衰老期间下降的单个蛋白质来复制抛物线率的恢复活力。其他工作表明，抛物性的感应效应可以由另一种随着年龄增长而增加的单个蛋白质复制。我们将通过对年龄和免疫刺激治疗的血浆蛋白反应的蛋白质组学分析来发现其他候选蛋白质。这些目标的成功将提供候选目标，以探索del妄的个体干预的候选目标，以使认知能力下降可逆，而不是在年轻人中，而不是为痴呆症的发作或进展做出贡献。